Sulfonylquinoxalone derivatives and related compounds as bradykinin antagonists

ABSTRACT

Disclosed are sulfonylquinoxalone acetamide derivatives useful as bradykinin antagonists.

This application under 35 U.S.C. § 119(e) claims the benefit of U.S.Provisional Application No. 60/378,206, filed May 3, 2002, which ishereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention is directed to certain1,2,3,4-tetrahydrosulfonylquinoxalone acetamide derivatives and relatedcompounds. These compounds are useful as bradykinin antagonists torelieve adverse symptoms, associated with bradykinin including pain,inflammation, bronchoconstriction, cerebral edema, etc.

REFERENCES

The following literature and patent publications are cited in thisapplication as superscript numbers.

-   -   ¹ J. G. Menke, et al., J. Biol. Chem., 269(34):21583-21586        (1994)    -   ² J. F. Hess, Biochem. Human B ₂ Receptor, Biophys. Res.        Commun., 184:260-268 (1992)    -   ³ Burch, et al., “Bradykinin Receptor Antagonists”, J. Med.        Chem., 30:237-269 (1990).    -   ⁴ Clark, W. G. “Kinns and the Peripheral Central Nervous        Systems”, Handbook of Experimental Pharmacology, Vol. XXV:        Bradykinin, Kallidin, and Kallikrein. Erdo, E. G. (Ed.), 311-322        (1979).    -   ⁵ Ammons, W. S., et al., “Effects of Intracardiac Bradykini on        T₂-T₅ Medial Spinothalamic Cells”, Amer. J. Phys., 249:147-152        (1985).    -   ⁶ Costello, A. H. et al., “Suppression of Carageenan-Induced        Hyperalgesia, Hyperthermia and Edema by a Bradykinin        Antagonist”, European Journal of Pharmacology, 171:259-263        (1989).    -   ⁷ Laneuville, et al., “Bradykinin Analog Blocks        Bradykinin-induced Inhibition of a Spinal Nociceptive Reflex in        the Rat”, European Journal of Pharmacology, 137:281-285 (1987).    -   ⁸ Steranka, et al., “Antinociceptive Effects of Bradykinin        Antagonists”, European Journal of Pharmacology, 136:261-262        (1987).    -   ⁹ Steranka, et al., “Bradykinin as a Pain Mediator: Receptors        are Localized to Sensory Neurons, and Antagonists have Analgesic        Actions”, Neurobiology, 85:3245-3249 (1987).    -   ¹⁰ Whalley, et al., in Naunyn Schmiederberg's Arch. Pharmacol.,        336:652-655 (1987).    -   ¹¹ Back, et al., “Determination of Components of the        Kallikrein-Kinin System in the Cerebrospinal Fluid of Patients        with Various Diseases”, Res. Clin. Stud. Headaches, 3:219-226        (1972).    -   ¹² Ness, et al., “Visceral pain: a Review of Experimental        Studies”, Pain, 41:167-234 (1990).    -   ¹³ Aasen, et al., “Plasma kallikrein Activity and Prekallikrein        Levels during Endotoxin Shock in Dogs”, Eur. Surg., 10:50-62        (1977).    -   ¹⁴ Aasen, et al., “Plasma Kallikrein-Kinin System in        Septicemia”, Arch. Surg., 118:343-346 (1983).    -   ¹⁵ Katori, et al., “Evidence for the Involvement of a Plasma        Kallikrein/Kinin System in the Immediate Hypotension Produced by        Endotoxin in Anaesthetized Rats”, Br. J. Pharmacol.,        98:1383-1391 (1989).    -   ¹⁶ Marceau, et al., “Pharmacology of Kinins: Their Relevance to        Tissue Injury and Inflammation”, Gen. Pharmacol., 14:209-229        (1982).    -   ¹⁷ Weipert, et al, Brit J. Pharm., 94:282-284 (1988).    -   ¹⁸ Haberland, “The Role of Kininogenases, Kinin Formation and        Kininogenase Inhibitor in Post Traumatic Shock and Related        Conditions”, Klinische Woochen-Schrift, 56:325-331 (1978).    -   ¹⁹ Ellis, et al., “Inhibition of Bradykinin-and        Kallikrein-Induced Cerebral Arteriolar Dilation by Specific        Bradykinin Antagonist”, Stroke, 18:792-795 (1987).    -   ²⁰ Kamitani, et al., “Evidence for a Possible Role of the Brain        Kallikrein-Kinin System in the Modulation of the Cerebral        Circulation”, Circ. Res., 57:545-552 (1985).    -   ²¹ Barnes, “Inflammatory Mediator Receptors and Asthma”, Am.        Rev. Respir. Dis., 135:S26-S31 (1987).    -   ²² Burch, et al., “Bradykinin Receptor Antagonists”, J. Med.        Chem., 30:237-269 (1990).    -   ²³ Fuller, et al., “Brakykinin-induced Bronchoconstriction in        Humans”, Am. Rev. Respir. Dis., 135:176-180 (1987).    -   ²⁴ Jin, et al., “Inhibition of Bradykinin-Induced        Bronchoconstriction in the Guinea-Pig by a Synthetic B₂ Receptor        Antagonist”, Br. J. Pharmacol., 97:598-602 (1989).    -   ²⁵ Polosa, et al., “Contribution of Histamine and Prostanoids to        Bronchoconstriction Provoked by Inhaled Bradykinin in Atopic        Asthma”, Allergy, 45:174-182 (1990).    -   ²⁶ Baumgarten, et al., “Concentrations of Glandular Kallikrein        in Human Nasal Secretions Increase During Experimentally Induced        Allergic Rhinitis”, J. Immunology, 137:1323-1328 (1986).    -   ²⁷ Proud, et al., “Nasal Provocation with Bradykinin Induces        Symptoms of Rhinitis and a Sore Throat”, Am. Rev. Respir Dis.,        137:613-616 (1988).    -   ²⁸ Steward and Vavrek in “Chemistry of Peptide Bradykinin        Antagonists” Basic and Chemical Research, R. M. Burch (Ed.),        pages 51-96 (1991).    -   ²⁹ Seabrook, et al., Expression of B1 and B2 Bradykinin Receptor        mRNA and Their Functional Roles in Sympathetic Ganglia and        Sensory Dorsal Root Ganglia Neurons from Wild-type and B2        Receptor Knockout Mice, Neuropharmacology, 36(7):1009-17 (1997)    -   ³⁰ Elguero, et al., Nonconventional Analgesics: Bradykinin        Antagonists, An. R. Acad. Farm., 63(1):173-90 (Spa) (1997)    -   ³¹ McManus, U.S. Pat. No. 3,654,275, Quinoxalinecarboxamide        Antiinflammatory Agents, issued Apr. 4, 1972.

All of the above identified publications are herein incorporated byreference in their entirety to the same extent as if each individualpublication was specifically and individually incorporated by referencein its entirety.

2. State of the Art

Bradykinin is known to be one of the most potent naturally occurringstimulators of C-fiber afferents mediating pain. It also is a potentvasodilator, edema-producing agent, and stimulator of various vascularand non-vascular smooth muscles in tissues such as uterus, gut andbronchiole. The kinin/kiniogen activation pathway has also beendescribed as playing a pivotal role in a variety of physiologic andpathophysiologic processes, being one of the first systems to beactivated in the inflammatory response and one of the most potentsimulators of: (i) phospholipase A₂ and, hence, the generation ofprostaglandins and leukotrienes; and (ii) phospholipase C and thus, therelease of inositol phosphates and diacylgylcerol. These effects aremediated predominantly via activation of BK receptors of the BK₂ type.

Bradykinin (BK) is a peptide composed of nine amino acides(Arg¹-Pro²-Pro³-Gly⁴-Phe⁵-Ser⁶-Pro⁷-Phe⁸-Arg⁹) (SEQ. ID. NO. 1) which,along with lysyl-BK (kallidin), is released from precursor kininogens byproteases termed kallikreins. Plasma kallikrein circulates as aninactive zymogen, from which active kallikrein is released by Hagemanfactor. Tissue kallikrein appears to be located predominantly on theouter surface of epithelial cell membranes at sites thought to beinvolved in transcellular electrolyte transport.

B2 receptors are receptors for bradykinin and kallidin; they predominateand are normally found in most tissues. B1 receptors are specific for[des-Arg⁹] bradykinin and [des-Arg¹⁰] kallidin. The B1 subtype isinduced by inflammatory processes. Bradykinin receptors have been clonedfor different species, notably the human B1 receptor (see J. G. Menke etal.¹, and human B2 receptor J. F. Hess²).

The distribution of receptor B1 is very limited since this receptor isonly expressed during states of inflammation. Two generations ofpeptidic antagonists of the B2 receptor have been developed. The secondgeneration has compounds two orders of magnitude more potent asanalgesics than first generation compounds and the most importantderivative was icatibant. The first non-peptidic antagonist of the B2receptor, described in 1993, has two phosphonium cations separated by amodified amino acid. Many derivatives of this di-cationic compound havebeen prepared. Another non-peptidic compound antagonist of B2 is thenatural product Martinelline. See Elguero³⁰. See also Seabrook²⁹.

Two major kinin precursor proteins, high molecular weight and lowmolecular weight kininogen are synthesized in the liver, circulate inplasma, and are found in secretions such as urine and nasal fluid. Highmolecular weight kininogen is cleaved by plasma kallikrein, yielding BK,or by tissue kallikrein, yielding kallidin. Low molecular weightkininogen, however, is a substrate only for tissue kallikrein. Inaddition, some conversion of kallidin to BK may occur inasmuch as theamino terminal lysine residue of kallidin is removed by plasmaaminopeptidases. Plasma half-lives for kinins are approximately 15seconds, with a single passage through the pulmonary vascular bedresulting in 80-90% destruction. The principle catabolic enzyme invascular beds is the dipeptidyl carboxypeptidase kininase II orangiotensin-converting enzyme (ACE). A slower acting enzyme, kininase I,or carboxypeptidase N, which removes the carboxyl terminal Arg,circulates in plasma in great abundance. This suggests that it may bethe more important catabolic enzyme physiologically. Des-Arg⁹-bradykininas well as des-Arg¹⁰-kallidin formed by kininase I acting on BK orkallidin, respectively, are acting BK₁ receptor agonists, but arerelatively inactive at the more abundant BK₂ receptor at which both BKand kallidin are potent agonists.

Direct application of bradykinin to denuded skin or intra-arterial orvisceral injection results in the sensation of pain in mammals includinghumans. Kinin-like materials have been isolated from inflammatory sitesproduced by a variety of stimuli. In addition, bradykinin receptors havebeen localized to nociceptive peripheral nerve pathways and BK has beendemonstrated to stimulate central fibers mediating pain sensation.Bradykinin has also been shown to be capable of causing hyperalgesia inanimal models of pain. See, Burch et al,³ and Clark, W. G.⁴

These observations have led to considerable attention being focused onthe use of BK antagonists as analgesics. A number of studies havedemonstrated that bradykinin antagonists are capable of blocking orameliorating both pain as well as hyperalgesia in mammals includinghumans. See, Ammons⁵, Clark⁴, Costello⁶, Lanuville⁷, Steranka⁸ andSteranka⁹.

Currently accepted therapeutic approaches to analgesia have significantlimitations. While mild to moderate pain can be alleviated with the useof non-steroidal anti-inflammatory drugs and other mild analgesics,severe pain such as that accompanying surgical procedures, burns andsevere trauma requires the use of narcotic analgesics. These drugs carrythe limitations of abuse potential, physical and psychologicaldependence, altered mental status and respiratory depression whichsignificantly limit their usefulness.

Prior efforts in the field of BK antagonists indicate that suchantagonists can be useful in a variety of roles. These include use inthe treatment of burns, perioperative pain, migraine and other forms ofpain, shock, central nervous system injury, asthma, rhinitis, prematurelabor, inflammatory arthritis, inflammatory bowel disease, etc. Forexample, Whalley¹⁰ has demonstrated that BK antagonists are capable ofblocking BK-induced pain in a human blister base model. This suggeststhat topical application of such antagonists would be capable ofinhibiting pain in burned skin, e.g., in severely burned patients thatrequire large doses of narcotics over long periods of time and for thelocal treatment of relatively minor burns or other forms of local skininjury.

The management of perioperative pain requires the use of adequate dosesof narcotic analgesics to alleviate pain while not inducing excessiverespiratory depression. Post-operative narcotic-induced hypoventilationpredisposes patients to collapse of segments of the lungs, a commoncause of post-operative fever, and frequently delays discontinuation ofmechanical ventilation. The availability of a potent non-narcoticparenteral analgesic could be a significant addition to the treatment ofperioperative pain. While no currently available BK antagonist has theappropriate pharmacodynamic profile to be used for the management ofchronic pain, frequent dosing and continuous infusions are alreadycommonly used by anesthesiologists and surgeons in the management ofperioperative pain.

Several lines of evidence suggest that the kallikrein/kinin pathway maybe involved in the initiation or amplification of vascular reactivityand sterile inflammation in migraine. (See, Back¹¹). Because of thelimited success of both prophylactic and non-narcotic therapeuticregimens for migraine as well as the potential for narcotic dependencein these patients, the use of BK antagonists offers a highly desirablealternative approach to the therapy of migraine.

Bradykinin is produced during tissue injury and can be found in coronarysinus blood after experimental occlusion of the coronary arteries. Inaddition, when directly injected into the peritoneal cavity, BK producesa visceral type of pain. (See, Ness¹²). While multiple other mediatorsare also clearly involved in the production of pain and hyperalgesia insettings other than those described above, it is also believed thatantagonists of BK have a place in the alleviation of such forms of painas well.

Shock related to bacterial infections is a major health problem. It isestimated that 400,000 cases of bacterial sepsis occur in the UnitedStates yearly; of those 200,000 progress to shock, and 50% of thesepatients die. Current therapy is supportive, with some suggestion inrecent studies that monoclonal antibodies to Gram-negative endotoxin mayhave a positive effect on disease outcome. Mortality is still high, evenin the face of this specific therapy, and a significant percentage ofpatents with sepsis are infected with Gram-positive organisms whichwould not be amenable to anti-endotoxin therapy.

Multiple studies have suggested a role for the kallikrein/kinin systemin the production of shock associated with endotoxin. See, Aasen¹³,Aasen¹⁴, Katori¹⁵ and Marceau¹⁶. Recent studies using newly available BKantagonists have demonstrated in animal models that these compounds canprofoundly affect the progress of endotoxic shock. (See, Weipert¹⁷).Less data is available regarding the role of BK and other mediators inthe production of septic shock due to Gram-positive organisms. However,it appears likely that similar mechanisms are involved. Shock secondaryto trauma, while frequently due to blood loss, is also accompanied byactivation of the kallikrein/kinin system. (See, Haberland¹⁸.)

Numerous studies have also demonstrated significant levels of activityof the kallikrein/kinin system in the brain. Both kallikrein and BKdilate cerebral vessels in animal models of CNS injury. (See Ellis¹⁹ andKamitani²⁰. Bradykinin antagonists have also been shown to reducecerebral edema in animals after brain trauma. Based on these data, it isbelieved that BK antagonists should be useful in the management ofstroke and head trauma.

Other studies have demonstrated that BK receptors are present in thelung, that BK can cause bronchoconstriction in both animals and man andthat a heightened sensitivity to the bronchoconstrictive effect of BK ispresent in asthmatics. Some studies have been able to demonstrateinhibition of both BK and allergen-induced bronchoconstriction in animalmodels using BK antagonists. These studies indicate a potential role forthe use of BK antagonists as clinical agents in the treatment of asthma.(See Barnes,²¹ Burch²², Fuller²³, Jin²⁴ and Polosa²⁵.) Bradykinin hasalso been implicated in the production of histamine and prostanoids tobronchoconstriction provoked by inhaled bradykinin in atopic asthma.²⁵Bradykinin has also been implicated in the production of symptoms inboth allergic and viral rhinitis. These studies include thedemonstration of both kallikrein and BK in nasal lavage fluids and thatlevels of these substances correlate well with symptoms of rhinitis.(See, Baumgarten²⁶, Jin²⁴, and Proud²⁷.)

In addition, studies have demonstrated that BK itself can cause symptomsof rhinitis. Stewart and Vavrek²⁸ discuss peptide BK antagonists andtheir possible use against effects of BK. A great deal of researcheffort has been expended towards developing such antagonists withimproved properties. However, notwithstanding extensive efforts to findsuch improved BK antagonists, there remains a need for additional andmore effective BK antagonists. Two of the major problems with presentlyavailable BK antagonists are their low levels of potency and theirextremely short durations of activity. Thus there is a special need forBK antagonists having increased potency and for duration of action.

U.S. Pat. No. 3,654,275³¹ teaches that certain1,2,3,4-tetrahydro-1-acyl-3-oxo-2-quinoxalinecarboxamides haveanti-inflammatory activity and describes the preparation of certainintermediates which can also be used as intermediates in the preparationof the compounds hereafter described.

In view of the above, compounds which are bradykinin antagonists wouldbe particularly advantageous in treating those diseases mediated bybradykinin.

SUMMARY OF THE INVENTION

This invention is directed, in part, to compounds which are bradykininantagonists and are useful to treat diseases or relieve adverse symptomsassociated with disease conditions in mammals mediated by bradykinin.Certain of the compounds exhibit increased potency and are expected toalso exhibit an increased duration of action.

In one embodiment, this invention provides compounds of Formula I:

wherein one of bonds characterized by

is a double bond and the other two are single bonds;

n is an integer from 0 to 4;

p is zero or one;

q is zero or one;

Y is selected from the group consisting of ═O, ═S, —OR⁸, —NHR⁸, ═NR⁸,—SR⁸, and, when Y is —NHR⁸ or ═NR⁸, R⁷ and R⁸, together with thenitrogen atoms to which they are attached, can form a heteroaryl, asubstituted heteroaryl, a unsaturated heterocyclic, or a substitutedunsaturated heterocyclic; provided that:

when Y is ═O, ═S, or ═NR⁸, then the bonds characterized by

between the 2-3 and 3-4 position are single covalent bonds and p is one;

when Y is —OR⁸, —SR⁸, or —NHR⁸ and p is zero, then the bondcharacterized by

between the 3-4 position is a double bond; or

when Y is —OR⁸, —SR⁸, or —NHR⁸ and p=1 and R⁷ is other than hydrogen,then the bond characterized by

between the 2-3 position is a double bond;

W is selected from the group consisting of O, S, and N, wherein:

when W is O or S, then q is zero; and when W is N, then q is one;

R is selected from the group consisting of aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic;

R¹ and R² are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl,substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclicand substituted heterocyclic, or R¹ and R² together with the nitrogenatom to which they are attached form a heteroaryl, substitutedheteroaryl, heterocyclic, or substituted heterocyclic;

each R³ is independently selected from the group consisting of alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, amino, substituted amino, cycloalkyl, substituted cycloalkyl,alkoxy, substituted alkoxy, aryl, substituted aryl, aryloxy, substitutedaryloxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substitutedheteroaryloxy, heterocyclic, substituted heterocyclic, heterocyclyloxy,substituted heterocyclyloxy, acyl, acyloxy, halogen, nitro, cyano,hydroxy, carboxy, —C(O)OR¹⁰ wherein R¹⁰ is alkyl, substituted alkyl,aryl, or substituted aryl, and —C(O)NR¹¹R¹² wherein R¹¹ and R¹² areindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, cycloalkyl, substitutedcycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic, or R¹¹ and R¹² together with the nitrogenatoms to which they are joined form a heteroaryl, substitutedheteroaryl, heterocyclic a substituted heterocyclic group;

or two or more of R³ together with the carbon atoms to which they arejoined form a fused ring cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, unsaturatedheterocyclic or substituted unsaturated heterocyclic;

R⁷ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl,aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic, acyl and acyloxy;

or R⁷ together with at least one of R³ and the nitrogen and carbon atomsto which they are joined forms a fused ring heteroaryl, substitutedheteroaryl, unsaturated heterocyclic or substituted unsaturatedheterocyclic;

R⁸ is selected from the group consisting of alkyl, substituted alkyl,alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic,substituted heterocyclic, acyl and acyloxy;

and pharmaceutically acceptable salts thereof;

with the proviso that when W═N and Y═O, at least R¹ and/or R² isselected from the group consisting of

-   -   I -alkylene-C(═O)R^(a), wherein alkylene is optionally        substituted and R^(a) is selected from the group consisting of        hydroxyl, —NR^(b)R^(b), —OR^(b), alkyl, substituted alkyl,        alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,        aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,        heteroaryl, substituted heterocyclyl, substituted heterocyclyl        wherein each R^(b) is independently selected from the group        consisting of hydrogen, alkyl, substituted alkyl, alkenyl,        substituted alkenyl, alkynyl, substituted alkynyl, aryl,        substituted aryl, cycloalkyl, substituted cycloalkyl,        heteroaryl, substituted heteroaryl, heterocyclic and substituted        heterocyclic;    -   II -alkylene-X^(a), wherein alkylene is optionally substituted        and X^(a) is selected from the group consisting of —OH, cyano,        and —NR^(b)R^(b) wherein each R^(b) is independently as defined        above;    -   III —NHR^(b), wherein R^(b) is as defined above;    -   IV —OR^(b), wherein R^(b) is as defined above;    -   V -alkylene-het^(a)-C(═O)—CH(R^(b))NR^(b)R^(b), wherein alkylene        is optionally substituted and het^(a) is a nitrogen containing        heterocycyl attached to the —C(O)— group through a ring nitrogen        atom of the het^(a) group and each R^(b) is as defined above;    -   VI -alklene-het^(a)-C(═O)-het^(b), wherein alkylene is        optionally substituted and het^(a) is as defined above and        het^(b) is a heterocyclyl;    -   VII -alkylene-R^(c)—NR^(b)C(═NR^(b))NR^(b)R^(b), wherein        alkylene is optionally substituted, each R^(b) is as defined        above and R^(c) is selected from the group consisting of aryl,        substituted aryl, cycloalkyl, substituted cycloalkyl,        heteroaryl, substituted heteroaryl, heterocyclic and substituted        heterocyclic;    -   VIII -alkylene-R^(c)—NR^(b)C(═O)—NR^(b)R^(b), wherein alkylene        is optionally substituted, each R^(b) is as defined above and        R^(c) is as defined above;    -   IX -alkylene-R^(c)-alkylene-C(═O)R^(b), wherein alkylene is        optionally substituted and R^(b) and R^(c) are as defined above;    -   X -alkylene-R^(c)—C(═O)-alkylene-(X^(b))_(n′), wherein alkylene        is optionally substituted, X^(b) is selected from the group        consisting of —OH, halo, cyano, and —NR^(b)R^(b), n′ is one        except when X^(b) is halo then n′ can be 1-3; and further        wherein each R^(b) is independently as defined above and R^(c)        is as defined above;    -   XI -alkylene-R^(c)—C(═O)—R^(d), wherein alkylene is optionally        substituted and R^(c) is selected from the group consisting of        aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,        heteroaryl, substituted heteroaryl, heterocyclic and substituted        heterocyclic and R^(d) is selected from the group consisting of        substituted alkyl, aryl, heteroaryl, heterocyclic and        cycloalkyl;    -   XII -alkylene-R^(c)—NR^(b)C(═O)R^(e) wherein alkylene is        optionally substituted, R^(b) and R^(c) are as defined above,        and where R^(e) is substituted alkyl, alkenyl, substituted        alkenyl, aryl, substituted aryl, cycloalkyl, substituted        heteroaryl    -   XIII -alkynylene-R^(d) where R^(d) is as defined above;    -   XIV or where R¹ and R² are joined, together with the nitrogen        atom bond thereto, to form a nitrogen containing substituted        heterocyclyl with 1 to 2 substituents selected from substituted        alkyl, heteroaryl, heterocyclyl;    -   XV -alkenylene-R^(d) where R^(d) is as defined above; and    -   XVI -alkylene-R^(c)—NR^(b)—C(═NR^(b))R^(b), wherein alkylene is        optionally substituted, and each of R^(b) and R^(c) are as        defined above;    -   with the further provisos that:

A. when W is N, R¹ is hydrogen, R² is benzyl, R⁷ is methyl, n is zero, pis one, and Y is ═O, then R is not 2,4,6-trimethylphenyl;

B. when W is N, R¹ and R⁷ are hydrogen, R² is 2-(pyrid-4-yl)ethy-1-yl, nis zero, p is one, and Y is ═O, then R is not 1-methylpyrazol-4-yl;

C. when W is N, R¹ and R⁷ are hydrogen, R² is benzyl, n is zero, p isone, and Y is ═O, then R is not 2,4-difluorophenyl;

D. when W is N, R¹, R² and R⁷ are hydrogen, n is zero, p is one, and Yis ═O, then R is not 2,4-difluorophenyl;

E. when W is N, R¹ is hydrogen, R² and R⁷ are 3-chlorobenzyl, n is zero,p is one, and Y is ═O, then R is not 4-chloro-2,5-dimethylphenyl;

F. when W is N, R¹ and R⁷ are hydrogen, R² is benzyl, n is zero, p isone, and Y is ═O, then R is not phenyl;

G. when W is N, R¹ and R⁷ are hydrogen, R² is phenyl, n is zero, p isone, and Y is ═O, then R is not quinolin-8-yl; and

H. when W is N, R¹ and R⁷ are hydrogen, R² is benzyl, n is zero, p isone, and Y is ═O, then R is not thien-2-yl;

and with the further proviso excluding the following known compounds:

I. when R¹ and R⁷ are hydrogen, R² is 2-methoxyphenyl, n is zero, p isone, and Y′ is ═O, then R is not 4-methylphenyl; and

J. when R¹ and R⁷ are hydrogen, R² is 2-ethoxyphenyl, n is zero, p isone, and Y′ is ═O, then R is not 4-methylphenyl.

Preferred R groups include, for example, phenyl; naphth-1-yl;5-dimethylamino-naphth-1-yl; 2-fluorophenyl; 2-chlorophenyl;2-cyanophenyl; 2-methylphenyl; 2-nitrophenyl; 2-trifluoromethylphenyl;3-chlorophenyl; 4-methylphenyl(tolyl); 2,5-dibromophenyl;4-bromo-2-ethylphenyl; 4-bromo-2-trifluoromethoxyphenyl;2,3-dichlorophenyl; 2,4-dichlorophenyl; 3,4-dichlorophenyl;2,5-dichlorophenyl; 3,5-dichlorophenyl; 2,6-dichlorophenyl;2-chloro-4-cyanophenyl; 2-chloro-4-fluorophenyl;3-chloro-2-methylphenyl; 2-chloro-6-methylphenyl;5-chloro-2-methoxyphenyl; 2-chloro-4-trifluoromethylphenyl;2,4-difluorophenyl; 5-fluoro-2-methylphenyl; 2,5-dimethoxyphenyl;2-methoxy-4-methylphenyl; 2-methoxy-5-bromophenyl;2-methoxy-5-methylphenyl; 2,5-dimethylphenyl; 2-methyl-5-nitrophenyl;3,5-di(trifluoromethyl)phenyl; 4-bromo-2,5-difluorophenyl;2,3,4-trichlorophenyl; 2,4,5-trichlorophenyl; 2,4,6-trichlorophenyl;2,4-dichloro-5-methylphenyl; 4-chloro-2,5-dimethylphenyl;2,4,6-tri(iso)propylphenyl; 2,4,6-trimethylphenyl;2,3,5-trimethyl-4-chlorophenyl; 2,3,6-trimethyl-4-methoxyphenyl;2,3,4,5,6-pentamethylphenyl; 5-chloro-1,3-dimethylpyrazol-4-yl;2-methoxycarbonyl-thiophen-3-yl; 2,3-dimethylimidazol-5-yl;2-methylcarbonylamino-4-methyl-thiazol-5-yl; quinolin-8-yl;thiophen-2-yl; 1-methylimidiazol-4-yl; 3,5-dimethylisoxazol-4-yl; andN-morpholino.

Particularly preferred R groups include 4-chloro-2,5-dimethylphenyl and2,3-dichlorophenyl.

When W is N, preferred R¹ groups include, for example,

2-[(4-amidino)phenyl]-1-(R)-(pyrrolidin-N-ylcarbonyl)eth-1-yl,

amino,

2-[N-(α-aminoacetyl)piperid-4-yl]eth-1-yl,

2-[4-(aminoethyleneamidino)phenyl]eth-1-yl,

2-[N-(1-amino-1-methylethylcarbonyl)piperid-4-yl]eth-1-yl,

1-(S)-carboxamide-2-(indol-3-yl)eth-1-yl,

carboxamidemethyl,

1-carboxamide-2-(S)-methyl-but-1-yl,

1-(S)-carboxamide-2-(phenyl)eth-1-yl,

1-(R)-carboxamide-2-(phenyl)eth-1-yl,

cyanomethyl,

2-(4-cyanophenyl)-1-(R)-(pyrrolidin-N-ylcarbonyl)eth-1-yl,

2-(4-cyanophenyl)-1-(S)-(pyrrolidin-N-ylcarbonyl)eth-1-yl,

2-(N-cyclopropylpiperidin-4-yl)-1-(R)-(pyrrolidin-N-ylcarbonyl)eth-1-yl,

1-(R)-1,3-di(benzyloxycarbonyl)prop-1-yl,

1-(S)-1,3-dicarboxamideprop-1-yl,

(2-dimethylamino)eth-1-yl,

3-(dimethylamino)prop-1-yl,

1-(S)-ethoxycarbonyleth-1-yl,

1-(R)-(1-N-ethylamino-carbonyl)-4-amino-n-butyl,

1-(S)-(1-N-ethylamino-carbonyl)-4-amino-n-butyl,

1-(R)-(1-N-ethylaminocarbonyl)-5-(t-butoxycarbonylamino)-pent-5-yl,

1-(S)-(1-N-ethylaminocarbonyl)-5-(t-butoxycarbonylamino)-pent-5-yl,

1-(R)-(1-N-ethylaminocarbonyl)-4-(N′-t-butoxycarbonylamino)-n-but-1-yl,

1-(S)-(1-N-ethylaminocarbonyl)-4-(N′-t-butoxycarbonylamino)-n-but-1-yl,

1-(R)-(1-N-ethylaminocarbonyl)-5-guanadino-n-pent-5-yl,

1-(S)-(1-N-ethylaminocarbonyl)-5-guanadino-n-pent-5-yl,

1-R,S-(1-N-ethylaminocarbonyl)-4-(N′-t-butoxycarbonyl)-guanadino-n-but-1-yl,

1-(R)-(1-N-ethylaminocarbonyl)-5-(N′-t-butoxycarbonylamino)-n-pent-5-yl,

1-(S)-(1-N-ethylaminocarbonyl)-5-(N′-t-butoxycarbonylamino)-n-pent-5-yl,

2-hydroxyeth-1-yl,

2-(4-hydroxyphenyl)-1-(S)-(methoxycarbonyl)eth-1-yl,

2-(4-hydroxyphenyl)-1-(S)-(isopropoxycarbonyl)eth-1-yl,

2-(4-hydroxyphenyl)-1-(R)-(methoxycarbonyl)eth-1-yl,

2-(N-hydroxypyrid-4-yl)eth-1-yl,

2-(imidazol-4-yl)eth-1-yl,

2-[4-(imidazolin-2-yl)phenyl]-1-(R)-(pyrrolidin-1-ylcarbonyl)eth-1-yl,

2-(indol-3-yl)eth-1-yl,

2-(indol-3-yl)-1-(S)-(methoxycarbonyl)eth-1-yl,

2-(indol-3-yl)-1-(R)-(methoxycarbonyl)eth-1-yl,

1-(R)-(isopropoxycarbonyl)-2-(phenyl)eth-1-yl,

methoxy,

1-(R)-(methoxycarbonyl)eth-1-yl,

methoxycarbonylmethyl,

methoxycarbonylphenylmethyl,

2-methoxyeth-1-yl,

1-(R)-(methoxycarbonyl)-2-(N-methylpiperidin-4-yl)eth-1-yl,

1-(R)-(methoxycarbonyl)-2-(N-methyl-1,2,3,6-tetrahydropyrid-4-yl)eth-1-yl,

1-(R)-(methoxycarbonyl)-2-pyrid-4-yl)eth-1-yl,

1-(R)-(N-methyl-N-ethylcarbamoyl)-3-(guanadino)prop-1-yl,

2-(N-methylpiperidin-4-yl)-1-(R)-(pyrrolidin-N-ylcarbonyl)eth-1-yl,

2-(N-methyl-1,2,5,6-tetrahydropyrid-4-yl)-1-(R)-(pyrrolidin-N-ylcarbonyl)eth-1-yl,

3-(2-methylthiazol-4-yl)-pyrazol-5-yl,

1-(R)-2-phenyl-1-(methoxycarbonyl)eth-1-yl,

1-(S)-2-phenyl-1-(methoxycarbonyl)eth-1-yl,

2-(phenyl)-1-(S)-(pyrrolidin-N-ylcarbonyl)eth-1-yl,

(piperidin-1-yl)carbonylmethyl,

1-(R)-(pyrrolidin-N-ylcarbonyl)-2-(4-amidino)phenyl-eth-1-yl,

1-(S)-(pyrrolidin-N-ylcarbonyl)-2-(4-amidino)phenyl-eth-1-yl,

1-(R)-(pyrrolidin-N-ylcarbonyl)-5-amino-n-pent-1-yl,

1-(S)-(pyrrolidin-N-ylcarbonyl)-5-amino-n-pent-1-yl,

1-(R)-(pyrrolidin-N-ylcarbonyl)-2-(4-biphenyl)eth-1-yl,

1-(S)-(pyrrolidin-N-ylcarbonyl)-2-(4-biphenyl)eth-1-yl,

1-(R)-(pyrrolidin-N-ylcarbonyl-2-(4-iodophenyl)eth-1-yl,

1-(S)-(pyrrolidin-N-ylcarbonyl-2-(4-iodophenyl)eth-1-yl,

1-(R)-(pyrrolidin-N-carbonyl)-4-(t-butoxycarbonylamino)-n-but-1-yl,

1-(S)-(pyrrolidin-N-carbonyl)-4-(t-butoxycarbonylamino)-n-but-1-yl,

1-(S)-(pyrrolidin-N-ylcarbonyl)-2-[4-(2-imidazolin-2-yl)phenyl]eth-1-yl,

2-(R)-(pyrrolidin-N-ylcarbonyl-3-phenylprop-2-yl,

1-(R)-(pyrrolidin-N-ylcarbonyl)-2-[4-(N-methylpiperidin-2-yl)eth-1-yl

1-(S)-(pyrrolidin-N-ylcarbonyl)-2-[4-(N-methylpiperidin-2-yl)phenyl)]eth-1-yl

1-(R)-(pyrrolidin-N-ylcarbonyl)-2-[N-methyl-1,2,5,6-tetrahydropyridin-4-yl)phen-4-yl)]eth-1-yl

1-(S)-(pyrrolidin-N-ylcarbonyl)-2-[N-methyl-1,2,5,6-tetrahydropyridin-4-yl)phen-4-yl)]eth-1-yl

1-(R)-(pyrrolidin-N-ylcarbonyl)-2-[4-(piperidin-2-yl)cyclohexyl)]eth-1-yl,

1-(S)-(pyrrolidin-N-ylcarbonyl)-2-[4-(piperidin-2-yl)cyclohexyl)]eth-1-yl,

1-(R)-(pyrrolidin-N-ylcarbonyl)-2-[N-(phenyl)-piperidin-4-yl)]eth-1-yl

1-(S)-(pyrrolidin-N-ylcarbonyl)-2-[N-(phenyl)-piperidin-4-yl)]eth-1-yl

1-(R)-(pyrrolidin-N-ylcarbonyl)-2-[N-(pyridin-4-yl)-piperidin-4-yl)]eth-1-yl

1-(S)-(pyrrolidin-N-ylcarbonyl)-2-[N-(pyridin-4-yl)-piperidin-4-yl)]eth-1-yl

1-(R)-(pyrrolidin-N-ylcarbonyl)-2-[4-(pyridin-4-yl)phenyl)]eth-1-yl

1-(S)-(pyrrolidin-N-ylcarbonyl)-2-[4-(pyridin-4-yl)phenyl)]eth-1-yl

1-(R)-(pyrrolidin-N-ylcarbonyl)-2-[4-(pyrid-2-yl)phenyl]eth-1-yl,

1-(S)-(pyrrolidin-N-ylcarbonyl)-2-[4-(pyrid-2-yl)phenyl]eth-1-yl,

1-(R)-(pyrrolidin-N-ylcarbonyl)-2-[4-(pyrimidin-2-yl)phenyl]eth-1-yl,

1-(S)-(pyrrolidin-N-ylcarbonyl)-2-[4-(pyrimidin-2-yl)phenyl]eth-1-yl,

1-(R)-(pyrrolidin-N-ylcarbonyl)-2-[4-(N-t-butoxycarbonylpyrrol-2-yl)phenyl]eth-1-yl

1-(S)-(pyrrolidin-N-ylcarbonyl)-2-[4-(N-t-butoxycarbonylpyrrol-2-yl)phenyl]eth-1-yl

1-(S)-(t-butoxycarbonyl)-2-(4-hydroxyphenyl)eth-1-yl,

3-t-butoxycarbonyl-1-methoxycarbonylprop-1-yl,

1-(S)-(t-butoxycarbonyl)-3-methylprop-1-yl,

1-(R)-(t-butoxycarbonyl)-3-methylprop-1-yl,

1-(R)-(t-butoxycarbonyl)-2-(phenyl)eth-1-yl,

1-(R)-1-pyrrolidin-N-ylcarbonyl-2-phenyleth-1-yl

2-phenyl-1-(R)-carboxy-eth-1-yl

2-[N-(α,α dinethylglycine)piperidin-4-yl]eth-1-yl

2-{4-(ethylamino-amidino)phenyl]eth-1-yl

1-(R)-(pyrrolidin-N-ylcarbonyl)-3-(guanadino)but-1-yl

1-(R)-(pyrrolidin-N-ylcarbonyl)-4-(N′-t-butoxycarbonyl)-guanadino-n-but-1-yl

1-(R)-(pyrrolidin-N-ylcarbonyl)-5-(N′-t-butoxycarbonylamino)-n-pent-5-yl

1-(R)-(pyrrolidin-N-ylcarbonyl)-4-amino-n-butyl

1-(R)-(pyrrolidin-N-ylcarbonyl)-4-guanadino-but-4-yl

1-(R)-(pyrrolidin-N-ylcarbonyl)-2-[4-(N-methyl-1,2,3,6-tetrahydropyridin-6-yl)phenyl)]eth-1-yl

1-(R)-(pyrrolidin-N-ylcarbonyl)-2-[4-(N-t-butoxycarbonylpyrrol-2-yl)phenyl]eth-1-yl

4-N-[(N′,N′-dimethylaminocarbonyl)amino-phen-4-yl]eth-1-yl

2-[N-(N′-morpholino-carbonyl)piperidin-4-yl]eth-1-yl

2-{N-[(2-(thiophen-2-yl)methylenecarbonyl]-piperidin-4-yl}eth-1-yl

2-[N-(3,5-dimethyloxazol-4-ylcarbonyl)piperidin-4-yl]eth-1-yl

2-[N-(furan-2-ylcarbonyl)-piperidin-4-yl]eth-1-yl

2-[N-(oxazol-5-yl-carbonyl)piperidin-4-yl]eth-1-yl

2-[N-(5-methylpyrazol-3-ylcarbonyl)piperidin-4-yl]eth-1-yl

2-[N-(1-methyl-3-t-butylpyrazol-5-ylcarbonyl)piperidin-4-yl]eth-1-yl

2-[N-(4-methylthiadiazol-5-ylcarbonyl)piperidin-4-yl]eth-1-yl

2-[N-(chloromethylene-carbonyl)piperidin-4-yl]eth-1-yl

2-[N-(benzylcarbonyl)-piperidin-4-yl]eth-1-yl

2-[N-(2-phenylethenyl-carbonyl)piperidin-4-yl]eth-1-yl

2-[N-(methoxymethylene-carbonyl)piperidin-4-yl]eth-1-yl

2-[N-(pyrazin-2-ylcarbonyl)piperidin-4-yl]eth-1-yl

2-[N-(isoquinolin-3-ylcarbonyl)piperidin-4-yl]eth-1-yl

2-[N-(pyrrolidin-5-one-2-ylcarbonyl)piperidin-4-yl]eth-1-yl

2-[N-(N′-acetylpyrrolidin-2-ylcarbonyl)piperidin-4-yl]eth-1-yl

2-[N-(dichloromethylenecarbonyl)piperidin-4-yl]eth-1-yl

4-[N-(pyrazin-2-ylcarbonyl)amino]pheneth-1-yl

4-[N-(isoquinolin-2-ylcarbonyl)amino]pheneth-1-yl

4-[N-(N′-acetylpyrrolidin-2-ylcarbonyl)amino]-pheneth-1-yl

4-[N-(1,2-benzothiadiazol-5-ylcarbonyl)amino]-pheneth-1-yl

4-[N-(benzofuran-5-ylcarbonyl)amino]pheneth-1-yl

4-[N-(3-methylisoxazol-5-ylcarbonyl)amino]-pheneth-1-yl

4-[N-(methoxyphen-3-ylcarbonyl)amino]pheneth-1-yl

4-[N-(thiophen-2-ylmethylenecarbonyl)amino]pheneth-1-yl

4-[N-(3,5-dimethyl-isoxazol-4-ylcarbonyl)-amino]pheneth-1-yl

4-[N-(2-(pyrid-3-yl)ethylcarbonyl)amino]pheneth-1-yl

4-[N-(furan-2-ylcarbon-yl)amino]pheneth-1-yl

4-[N-(isoxazol-5-ylcar-bonyl)amino]pheneth-1-yl

4-[N-(3-methylpyrazol-5-yl-5-ylcarbonyl)amino]-pheneth-1-yl

4-[N-(1-methyl-3-t-butyl-pyrazol-5-ylcarbonyl)-amino]pheneth-1-yl

4-[N-(4-methyl-1,2,3-thiadiazol-5-ylcarbonyl)-amino]-pheneth-1-yl

4-[N-(chloromethylene-carbonyl)amino]pheneth-1-yl

4-[N-(chlorophen-2-ylcarbonyl)amino]pheneth-1-yl

4-[N-(phenylcarbonyl)amino]pheneth-1-yl

4-[N-(pyrid-2-ylcarbonyl)-aminopheneth-1-yl

4-[N-(2-phenylethenyl-carbonyl)amino]pheneth-1-yl

4-[N-(2-phenylethenyl-carbonyl)amino]pheneth-1-yl

4-[N-(fluorophen-2-ylcarbonyl)amino]pheneth-1-yl

4-[N-(methoxymethylenecarbonyl)amino]pheneth-1-yl

4-[N-(dichloromethylene-carbonyl)amino]pheneth-1-yl

4-[N-(methylenedioxy-phen-4-ylcarbonyl)amino]-pheneth-1-yl

1-[(R)-(pyrrolidin-N-ylcarbonyl)]-2-[N-methylpyrid-2-yl)phen-4-yl]eth-1-yl

1-[(R)-(pyrrolidin-N-ylcarbonyl)]-2-[(N-methylpyrid-4-yl)phen-4-yl]eth-1-yl

1-[(R)-(pyrrolidin-N-ylcarbonyl)]-2-[(N-methylpyrid-4-yl)phen-4-yl]eth-1-yl

1-[(R)-(pyrrolidin-N-ylcarbonyl)]-2-[1-(piperidin-2-yl)phen-4-yl]eth-1-yl

1-(R)-(pyrrolidin-N-ylcarbonyl)-2-[4-(N-methylpyrid-4-yl)phen-1-yl)eth-1-yl

4-(pyridin-2-yl)but-3-yn-1-yl and

(benzoimidazol-2-ylamino)eth-1-yl.

When W is N, preferred R² groups include hydrogen, methyl, ethyl,iso-propyl, 2-methoxyeth-1-yl, and pyrid-3-ylmethyl.

In another preferred embodiment, when W is N, R¹ and R² are joined,together with the nitrogen atom to which they are bound, to form anoptionally substituted heterocyclic including, by way of example,4-(2-aminoethyl)piperidin-1-yl;4-[2-(N-t-butoxycarbonylamino)ethyl]-piperidin-1-yl; and1-(pyridin-2-yl)piperazin-4-yl.

A particularly preferred R² group is hydrogen.

Preferred R³ groups include, by way of example, chloro, fluoro andmethyl. In one preferred embodiment, the 1,2,3,4-quinoxaline ring isdisubstituted at the 6 and 7 positions to provide for 6,7-dichloro;6,7-difluoro and 6,7-dimethyl substitution.

Most preferably, n is zero (i.e., all of the R³ groups are hydrogen).

Preferred R⁷ groups include hydrogen, methyl, benzyl,t-butoxycarbonyl-methyl; and the like.

In a particularly preferred embodiment, W is nitrogen, Y is ═O, n iszero (all R³ groups are hydrogen), p is one, q is one and R² and R⁷ arehydrogen. Such compounds are represented by Formula II as follows:

where R and R¹ are as defined above; and pharmaceutically acceptablesalts thereof.

The present invention further provides intermediates for the compoundsof Formula I which can be represented by Formula III below:

wherein R³, R⁷, n, p, Y and the

bond line are as defined in Claim 1 and X is selected from the groupconsisting of —NR¹R² wherein R¹ and R² are joined, together with thenitrogen atom bond thereto, to form a nitrogen containing substitutedheterocyclyl with 1 to 2 substituents selected from the group consistingof substituted alky, heteroaryl, and heterocyclyl, or X is —OR¹⁰ whereinR¹⁰ is hydrogen or lower alkyl.

In those cases where the compounds of Formulas I-III exist as optical orgeometric isomers, the above formulas are intended to represent isomermixtures and also the individual BK antagonist or intermediate isomers.Formulas I-III are also intended to represent the individual isomers aswell as mixtures thereof; both of which are encompassed within the scopeof this invention.

Compounds within the scope of this invention include those set forth inTable I as follows: TABLE I

(R², R³, R^(3a), and R⁷ are all hydrogen unless otherwise specified) * RR¹ R², R³, R^(3a), R⁷ GP # Cpd. No. R & S 4-chloro-2,5-dimethyl-phenyl1-(R)-1-pyrrolidin-N-yl- I 5 carbonyl-2-phenyleth-1-yl R & S4-chloro-2,5-dimethyl-phenyl (piperidin-1-yl)carbonylmethyl I 6 R & S4-chloro-2,5-dimethyl-phenyl 2-hydroxyeth-1-yl II 11 R or S4-chloro-2,5-dimethyl-phenyl 1-(R)-2-phenyl-1-(meth- I 12oxycarbonyl)eth-1-yl R & S 4-chloro-2,5-dimethyl-phenyl(2-dimethylamino)eth-1-yl II 16 R & S 4-chloro-2,5-dimethyl-phenyl1-(R)-(methoxycarbonyl)-2-(N-meth- 46 ylpiperidin-4-yl)eth-1-yl R & S4-chloro-2,5-dimethyl-phenyl 1-(R)-1,3-di(benzyloxy- I 48carbonyl)prop-1-yl R & S 4-chloro-2,5-dimethyl-phenyl1-(R)-(iso-propoxycarbonyl)-2-(phe- I 49 nyl)eth-1-yl R & S4-chloro-2,5-dimethyl-phenyl 1-(R)-(methoxycarbonyl)eth-1-yl I 50 R & S4-chloro-2,5-dimethyl-phenyl 1-(R)-(methoxycarbonyl)-2-py- I 51rid-4-yl)eth-1-yl R & S 4-chloro-2,5-dimethyl-phenyl1-(R)-(methoxycarbonyl)-2-(N-meth- I 52yl-1,2,3,6-tetrahydropyrid-4-yl)eth-1-yl R or S4-chloro-2,5-dimethyl-phenyl 1-(R)-(methoxycarbonyl)-2-(N-meth- I 53ylpiperidin-4-yl)eth-1-yl R & S 4-chloro-2,5-dimethyl-phenyl1-(S)-(pyrrolidin-N-ylcarbonyl)-2-[4-(2-imi- I 54 dazolin-2-yl)phe-nyl]eth-1-yl R & S 4-chloro-2,5-dimethyl-phenyl1-(S)-(t-butoxycarbonyl)-3-meth- I 55 ylbut-1-yl R & S4-chloro-2,5-dimethyl-phenyl 1-(R)-(t-butoxycarbonyl)-3-meth- I 56ylprop-2-yl R & S 4-chloro-2,5-dimethyl-phenyl1-(S)-(t-butoxycarbonyl)-2-(4-hy- I 57 droxyphenyl)eth-1-yl R & S4-chloro-2,5-dimethyl-phenyl 1-(R)-(t-butoxycarbonyl)-2-(phe- I 58nyl)eth-1-yl R & S 4-chloro-2,5-dimethyl-phenyl1-(S)-carboxamide-2-(indol-3-yl)eth-1-yl I 59 R & S4-chloro-2,5-dimethyl-phenyl 1-(R)-carboxamide-2-(phenyl)eth-1-yl I 60 R& S 4-chloro-2,5-dimethyl-phenyl 1-(S)-carboxamide-2-(S)-meth- I 61ylbut-1-yl R & S 4-chloro-2,5-dimethyl-phenyl 1-(S)-carboxamide-2-(phe-I 62 nyl)eth-1-yl R & S 4-chloro-2,5-dimethyl-phenyl1-(S)-ethoxycarbonyleth-1-yl I 63 R & S 4-chloro-2,5-dimethyl-phenyl1-(S)-1,3-dicarboxamide prop-1-yl I 66 R & S4-chloro-2,5-dimethyl-phenyl2-(N-cyclopropyl-piperidin-4-yl)-1-(R)-(pyr- I 71 rolidin-N-yl-carbonyl)eth-1-yl R & S 4-chloro-2,5-dimethyl-phenyl2-(N-methyl-1,2,5,6-tetra- I 75 hydropyrid-4-yl)-1-(R)-(pyr-rolidin-N-ylcarbonyl)eth-1-yl R & S 4-chloro-2,5-dimethyl-phenyl2-(N-methylpiperidin-4-yl)-1-(R)-(pyr- I 78 rolidin-N-yl-carbonyl)eth-1-yl R & S 4-chloro-2,5-dimethyl-phenyl2-(4-cyanophenyl)-1-(R)-(pyr- I 85 rolidin-N-ylcarbonyl)eth-1-yl R & S4-chloro-2,5-dimethyl-phenyl 2-(4-cyanophenyl)-1-(S)-(pyr- I 86rolidin-N-ylcarbonyl)eth-1-yl R & S 4-chloro-2,5-dimethyl-phenyl2-(4-hydroxyphenyl)-1-(S)-(meth- I 87 oxycarbonyl)eth-1-yl R & S4-chloro-2,5-dimethyl-phenyl 2-(4-hydroxyphenyl)-1-(S)-(t-butoxy- I 88carbonyl)eth-1-yl R & S 4-chloro-2,5-dimethyl-phenyl2-(4-hydroxyphenyl)-1-(R)-(meth- I 89 oxycarbonyl)eth-1-yl R & S4-chloro-2,5-dimethyl-phenyl 2-(indol-3-yl)-1-(S)-(meth- I 92oxycarbonyl)eth-1-yl R & S 4-chloro-2,5-dimethyl-phenyl2-(indol-3-yl)-1-(R)-(meth- I 93 oxycarbonyl)eth-1-yl R & S4-chloro-2,5-dimethyl-phenyl 2-(phenyl)-1-(S)-(pyrrolidin-N-yl- I 94carbonyl)eth-1-yl R & S 4-chloro-2,5-dimethyl-phenyl2-(pyrid-4-yl)-1-(R)-(pyrrolidin-N-yl- I 104 carbonyl)eth-1-yl R & S4-chloro-2,5-dimethyl-phenyl 2-phenyl-1-(S)-(methoxy- I 110carbonyl)eth-1-yl R & S 4-chloro-2,4-dimethyl-phenyl2-phenyl-1-(R)-carboxy-eth-1-yl I 111 R & S 4-chloro-2,5-dimethyl-phenyl2-[N-(α,α dimethyl V 115 glycine)piperidin-4-yl]eth-1-yl R & S4-chloro-2,5-dimethyl-phenyl 2-[N-(α-aminoacetyl)piperidin-4-yl]eth-1-ylV 116 R or S 4-chloro-2,5-dimethyl-phenyl2-[4-(imidazolin-2-yl)phenyl]-1-(R)-(pyr- I 121 rolidin-1-yl-carbonyl)eth-1-yl R & S 4-chloro-2,5-dimethyl-phenyl3-(dimethylamino)prop-1-yl II 123 R & S 4-chloro-2,5-dimethyl-phenyl3-t-butoxycarbonyl-1-meth- I 125 oxycarbonylprop-1-yl R & S4-chloro-2,5-dimethyl-phenyl amino III 129 R & S4-chloro-2,5-dimethyl-phenyl 2-{4-(ethylamino- VII 130amidino)phenyl]eth-1-yl R & S 4-chloro-2,5-dimethyl-phenyl methylcarboxamide I 134 R & S 4-chloro-2,5-dimethyl-phenyl cyanomethyl II 135R or S 4-chloro-2,5-dimethyl-phenyl2-[(4-imidazolin-2-yl)phenyl]-1-(R)-(pyr- I 139 rolidin-N-yl-carbonyl)eth-1-yl R & S 4-chloro-2,5-dimethyl-phenyl 1-methoxy R² =methyl IV 140 R & S 4-chloro-2,5-dimethyl-phenyl 1-(R)-meth- I 141oxycarbonylphenylmethyl R & S 4-chloro-2,5-dimethyl-phenylmethoxycarbonylmethyl I 142 R or S 4-chloro-2,5-dimethyl-phenyl2-[(4-amidino)phenyl]-1-(R)-(pyr- I 169 rolidin-N-ylcarbonyl)eth-1-yl Ror S 4-chloro-2,5-dimethyl-phenyl 1-(R)-(pyrrolidin-N-yl- I 170carbonyl)-3-(guanadino)but-1-yl R or S 4-chloro-2,5-dimethyl-phenyl1-(R)-(pyrrolidin-N-yl- I 172 carbonyl)-5-amino-n-pent-1-yl R & S4-chloro-2,5-dimethyl-phenyl 1-(R)-(pyrrolidin-N-yl- I 173carbonyl)-4-(N′-t-butoxy- carbonyl)-guanadino-n-but-1-yl R or S4-chloro-2,5-dimethyl-phenyl 1-(R)-(pyrrolidin-N-yl- I 174carbonyl)-5-(N′-t-butoxy- carbonylamino)-n-pent-5-yl R or S4-chloro-2,5-dimethyl-phenyl 1-(R)-(pyrrolidin-N-yl- I 175carbonyl)-4-amino-n-butyl R or S 4-chloro-2,5-dimethyl-phenyl1-(R)-(pyrrolidin-N-yl- I 176 carbonyl)-4-(N′-t-butoxy-carbonylamino)-n-but-1-yl R or S 4-chloro-2,5-dimethyl-phenyl1-(R)-(pyrrolidin-N-yl- I 177 carbonyl)-2-(4-ami- dino)phenyl-eth-1-yl Ror S 4-chloro-2,5-dimethyl-phenyl 1-(R)-(pyrrolidin-N-yl- I 178carbonyl)-4-guanadino-but-4-yl R & S 4-chloro-2,5-dimethyl-phenyl —NR¹R²= 4-(2-amino- XIV 179 ethyl)-piperidin-1-yl R or S4-chloro-2,5-dimethyl-phenyl 1-(R)-(pyrrolidin-N-yl- I 180carbonyl)-2-(4-iodophenyl)-eth-1-yl R & S 4-chloro-2,5-dimethyl-phenyl—NR¹R² = 4-[2-(N-t-butoxy- XIV 182 carbonylamino)-ethyl]-pipe-ridin-1-yl R or S 4-chloro-2,5-dimethyl-phenyl 1-(R)-(pyrrolidin-N-yl- I187 carbonyl)-4-amino-n-butyl R or S 4-chloro-2,5-dimethyl-phenyl1-(R)-(pyrrolidin-N-yl- I 189 carbonyl)-5-(t-butoxy-carbonylamino)-pent-5-yl R & S 4-chloro-2,5-dimethyl-phenyl —NR¹R² =1-(py- XIV 190 ridin-2-yl)-piperazin-4-yl R or S4-chloro-2,5-dimethyl-phenyl 1-(R)-(pyrrolidin-N-yl- I 191carbonyl)-5-amino-n-pent-1-yl R or S 4-chloro-2,5-dimethyl-phenyl1-(R)-(pyrrolidin-N-yl- I 198 carbonyl)-4-(t-butoxy-carbonylamino)-n-but-1-yl R or S 4-chloro-2,5-dimethyl-phenyl1-(R)-(pyrrolidin-N-yl- I 200 carbonyl)-2-(4-iodophenyl)-eth-1-yl R or S4-chloro-2,5-dimethyl-phenyl 1-(R)-(pyrrolidin-N-yl- I 202carbonyl)-2-[4-(pyrid-2-yl)phe- nyl)eth-1-yl R or S4-chloro-2,5-dimethyl-phenyl 1-(R)-(pyrrolidin-N-yl- I 203carbonyl)-2-[4-(pyrid-2-yl)phe- nyl)]eth-1-yl R or S4-chloro-2,5-dimethyl-phenyl 1-(R)-(pyrrolidin-N-yl- I 205carbonyl)-2-[4-(pyrimidin-2-yl)phe- nyl)]eth-1-yl R or S4-chloro-2,5-dimethyl-phenyl 1-(R)-(pyrrolidin-N-yl- I 206carbonyl)-2-[4-(pyrimidin-2-yl)phe- nyl)]eth-1-yl R or S4-chloro-2,5-dimethyl-phenyl 1-(R)-(pyrrolidin-N-yl- I 211carbonyl)-2-[4-(piperidin-2-yl)cyclo- hexyl)]eth-1-yl R or S4-chloro-2,5-dimethyl-phenyl 1-(R)-(pyrrolidin-N-yl- I 212carbonyl)-2-[4-(piperidin-2-yl)cyclo- hexyl)]eth-1-yl R or S4-chloro-2,5-dimethyl-phenyl 1-(R)-(pyrrolidin-N-yl- I 213carbonyl)-2-[4-(N-methyl-1,2,3,6-tetra- hydropyridin-6-yl)phe-nyl)]eth-1-yl R or S 4-chloro-2,5-dimethyl-phenyl1-(R)-(pyrrolidin-N-yl- I 214 carbonyl)-2-[4-(N-methyl-1,2,3,6-tetra-hydropyridin-6-yl)phe- nyl)]eth-1-yl R or S 4-hcloro-2,5-dimethyl-phenyl1-(R)-(pyrrolidin-N-yl- I 215 carbonyl)-2-[4-(pyridin-4-yl)phe-nyl)]eth-1-yl R or S 4-chloro-2,5-dimethyl-phenyl1-(R)-(pyrrolidin-N-yl- I 216 carbonyl)-2-[4-(pyridin-4-yl)phe-nyl)]eth-1-yl R or S 4-chloro-2,5-dimethyl-phenyl1-(R)-(pyrrolidin-N-yl- I 218 carbonyl)-2-[N-(phenyl)-piperidin-4-yl)]eth-1-yl R or S 4-chloro-2,5-dimethyl-phenyl1-(R)-(pyrrolidin-N-yl- I 219 carbonyl)-2-[N-(phenyl)-pipe-ridin-4-yl)]eth-1-yl R or S 4-chloro-2,5-dimethyl-phenyl1-(R)-(pyrrolidin-N-yl- I 220 carbonyl)-2-[N-(pyridin-4-yl)-pipe-ridin-4-yl)]eth-1-yl R or S 4-chloro-2,5-dimethyl-phenyl1-(R)-(pyrrolidin-N-yl- I 221 carbonyl)-2-[N-(pyridin-4-yl)-pipe-ridin-4-yl)]eth-1-yl R or S 4-chloro-2,5-dimethyl-phenyl1-(R)-(pyrrolidin-N-yl- I 239 carbonyl)-2-[N-methyl-1,2,5,6-tetra-hydropyridin-4-yl)-phen-4-yl)]eth-1-yl R or S4-chloro-2,5-dimethyl-phenyl 1-(R)-(pyrrolidin-N-yl- I 242carbonyl)-2-[N-methyl-1,2,5,6-tetra-hydropyridin-4-yl)-phen-4-yl)]eth-1-yl R or S4-chloro-2,5-dimethyl-phenyl 1-(R)-(pyrrolidin-N-yl- I 243carbonyl)-2-(4-biphenyl)eth-1-yl R or S 4-chloro-2,5-dimethyl-phenyl1-(R)-(pyrrolidin-N-yl- I 245 carbonyl)-2-(4-biphenyl)eth-1-yl R & S4-chloro-2,5-dimethyl-phenyl1-(R)-(pyrrolidin-N-ylcarbonyl)-2-[4-(N-t-butoxy- I 246carbonylpyrrol-2-yl)phe- nyl]eth-1-yl R & S 4-chloro-2,5-dimethyl-phenyl4-N-[(N′,N′-dimethyl-amino- VIII 268 carbonyl)amino-phen-4-yl]eth-1-yl R& S 4-chloro-2,5-dimethyl-phenyl 2-[N-(methylcarbonyl- IX 272methylene)piperidin-4-yl]eth-1-yl R & S 2,3-dichlorophenyl2-(N′,N′-dimethyl-amino)eth-1-yl II 278 R & S4-chloro-2,5-dimethyl-phenyl 2-[N-(N′-morpholino- VI 280carbonyl)piperidin-4-yl]eth-1-yl R & S 4-chloro-2,5-dimethyl-phenyl2{N-[(2-(thiophen-2-yl)meth- XI 281 ylenecarbonyl]-pipe-ridin-4-yl}eth-1-yl R & S 4-chloro-2,5-dimethyl-phenyl2-[N-(3,5-dimethyloxazol-4-yl- XI 282 carbonyl)piperidin-4-yl]eth-1-yl R& S 4-chloro-2,5-dimethyl-phenyl 2[N-(furan-2-ylcarbonyl)-pipe- XI 283ridin-4-yl]eth-1-yl R & S 4-chloro-2,5-dimethyl-phenyl2-[N-(oxazol-5-yl- XI 284 carbonyl)piperidin-4-yl]eth-1-yl R & S4-chloro-2,5-dimethyl-phenyl 2-[N-(5-methylpyrazol-3-yl- XI 285carbonyl)piperidin-4-yl]eth-1-yl R & S 4-chloro-2,5-dimethyl-phenyl2-[N-(1-methyl-3-t-butyl- XI 286 pyrazol-5-yl-carbonyl)piperidin-4-yl]eth-1-yl R & S 4-chloro-2,5-dimethyl-phenyl2-[N-(4-methylthiadiazol-5-yl- XI 287 carbonyl)piperidin-4-yl]eth-1-yl R& S 4-chloro-2,5-dimethyl-phenyl 2-[N-(chloromethylene- X 288carbonyl)piperidin-4-yl]eth-1-yl R & S 4-chloro-2,5-dimethyl-phenyl2-[N-(benzylcarbonyl)-pipe- XI 289 ridin-4-yl]eth-1-yl R & S4-chloro-2,5-dimethyl-phenyl 2-[N-(2-phenylethenyl- XI 292carbonyl)piperidin-4-yl]eth-1-yl R & S 4-chloro-2,5-dimethyl-phenyl2-[N-(methoxymethylene- XI 293 carbonyl)piperidin-4-yl]eth-1-yl R & S4-chloro-2,5-dimethyl-phenyl 2-[N-(pyrazin-2-yl- XI 294carbonyl)piperidin-4-yl]eth-1-yl R & S 4-chloro-2,5-dimethyl-phenyl2-[N-(isoquinolin-3-yl- XI 295 carbonyl)piperidin-4-yl]eth-1-yl R & S4-chloro-2,5-dimethyl-phenyl 2-[N-(pyrrolidin-5-one-2-yl- XI 296carbonyl)piperidin-4-yl]eth-1-yl R & S 4-chloro-2,5-dimethyl-phenyl2-[N-(N′-acetylpyrrolidin-2-yl- XI 297 carbonyl)piperidin-4-yl]eth-1-ylR & S 4-chloro-2,5-dimethyl-phenyl 2-[N-(dichloromethylene- XI 298carbonyl)piperidin-4-yl]eth-1-yl R & S 4-chloro-2,5-dimethyl-phenyl4-[N-(pyrazin-2-yl- XII 301 carbonyl)amino]pheneth-1-yl R & S4-chloro-2,5-dimethyl-phenyl 4-[N-(isoquinolin-2-yl- XII 302carbonyl)amino]pheneth-1-yl R & S 4-chloro-2,5-dimethyl-phenyl4-[N-(N′-acetylpyrrolidin-2-yl- XII 303 carbonyl)amino]-pheneth-1-yl R &S 4-chloro-2,5-dimethyl-phenyl 4-[N-(1,2-benzothiadiazol-5-yl- XII 304carbonyl)amino]-pheneth-1-yl R & S 4-chloro-2,5-dimethyl-phenyl4-[N-(benzofuran-5-yl XII 305 carbonyl)amino]pheneth-1-yl R & S4-chloro-2,5-dimethyl-phenyl 4-[N-(3-methylisoxazol-5-yl XII 306carbonyl)amino]-pheneth-1-yl R & S 4-chloro-2,5-dimethyl-phenyl4-[N-(N-morpholino- XII 307 carbonyl)amino]pheneth-1-yl R & S4-chloro-2,5-dimethyl-phenyl 4-[N-(methoxyphen-3-yl XII 308carbonyl)amino]pheneth-1-yl R & S 4-chloro-2,5-dimethyl-phenyl4-[N-(thiophen-2-yl- XII 309 methylenecarbonyl)amino]pheneth-1-yl R & S4-chloro-2,5-dimethyl-phenyl 4-[N-(3,5-dimethyl-isoxazol-4-yl- XII 310carbonyl)-amino]pheneth-1-yl R & S 4-chloro-2,5-dimethyl-phenyl4-[N-(2-(pyrid-3-yl)eth- XII 311 ylcarbonyl)amino]pheneth-1-yl R & S4-chloro-2,5-dimethyl-phenyl 4-[N-(furan-2-ylcarbon- XII 312yl)amino]pheneth-1-yl R & S 4-chloro-2,5-dimethyl-phenyl4-[N-(isoxazol-5-ylcar- XII 313 bonyl)amino]pheneth-1-yl R & S4-chloro-2,5-dimethyl-phenyl 4-[N-(3-methylpyrazol-5-yl-5-yl- XII 314carbonyl)amino]-pheneth-1-yl R & S 4-chloro-2,5-dimethyl-phenyl4-[N-(1-methyl-3-t-butyl- XII 315 pyrazol-5-ylcarbonyl)-ami-no]pheneth-1-yl R & S 4-chloro-2,5-dimethyl-phenyl4-[N-(4-methyl-1,2,3-thia- XII 316diazol-5-ylcarbonyl)-amino]pheneth-1-yl R & S4-chloro-2,5-dimethyl-phenyl 4-[N-(chloromethylene- XII 317carbonyl)amino]pheneth-1-yl R & S 4-chloro-2,5-dimethyl-phenyl4-[N-(chlorophen-2-ylcar- XII 318 bonyl)amino]pheneth-1-yl R & S4-chloro-2,5-dimethyl-phenyl 4-[N-(phenylcarbonyl)-amino]phen- XII 319eth-1-yl R & S 4-chloro-2,5-dimethyl-phenyl4-[N-(pyrid-2-ylcarbonyl)-amino- XII 321 pheneth-1-yl R & S4-chloro-2,5-dimethyl-phenyl 4-[N-(pyrid-4-ylcar- XII 322bonyl)amino]pheneth-1-yl R & S 4-chloro-2,5-dimethyl-phenyl4-[N-(2-phenylethenyl- XII 325 carbonyl)amino]pheneth-1-yl R & S4-chloro-2,5-dimethyl-phenyl 4-[N-(fluorophen-2-ylcar- XII 326bonyl)amino]pheneth-1-yl R & S 4-chloro-2,5-dimethyl-phenyl4-[N-(methoxymethylene- XII 327 carbonyl)amino]pheneth-1-yl R & S4-chloro-2,5-dimethyl-phenyl 4-[N-(dichloromethylene- XII 330carbonyl)amino]pheneth-1-yl R & S 4-chloro-2,5-dimethyl-phenyl4-[N-(methylenedioxy-phen-4-yl- XII 331 carbonyl)amino]-pheneth-1-yl Ror S 4-chloro-2,5-dimethyl-phenyl 1-[(R)-(pyrrolidin-N-yl- I 332carbonyl)]-2-[N-meth- yl-pyrid-2-yl)phen-4-yl]eth-1-yl R or S4-chloro-2,5-dimethyl-phenyl 1-[(R)-(pyrrolidin-N-yl- I 333carbonyl]-2-[(N-methyl- pyrid-4-yl)phen-4-yl]eth-1-yl R or S4-chloro-2,5-dimethyl-phenyl 1-[(R)-(pyrrolidin-N-yl- I 334carbonyl)]-2-[1-(piperidin-2-yl)phen-4-yl]eth-1-yl R or S4-chloro-2,5-dimethyl-phenyl 1-(R)-(pyrrolidin-N-yl- R² = methyl I 336carbonyl)-2-[4-(N-meth- ylpyrid-4-yl)phen-1-yl)eth-1-yl R4-chloro-2,5-dimethylphenyl 2-(benzo- II 346 imidazol-2-ylamino)eth-1-ylR 4-chloro-2,5-dimethylphenyl 3-(benzoimidazol-2-yl- II 347amino)prop-1-yl R & S 4-chloro-2,5-dimethylphenyl4-(pyridin-2-yl)but-3-yn-1-yl XIII 356 R & S 4-chloro-2,5-dimethylphenyl4-(pyridin-4-yl)but-3-yn-1-yl XIII 357Specific compounds within the scope of this invention include thefollowing:

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-1-pyrrolidin-N-ylcarbonyl-2-phenyleth-lyl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[(piperidin-1-yl)carbonylmethyl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(2-hydroxyeth-1-yl)acetamide

2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-2-phenyl-1-(methoxycarbonyl)eth-1-yl]acetamide

2-[2-(S orR)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-2-phenyl-1-(methoxycarbonyl)eth-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[(2-dimethylamino)eth-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(methoxycarbonyl)-2-(N-methylpiperidin-4-yl)eth-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-1,3-di(benzyloxycarbonyl)prop-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(isopropoxycarbonyl)-2-(phenyl)eth-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(methoxycarbonyl)eth-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-methoxycarbonyl-2-pyrid-4-yl)eth-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(methoxycarbonyl)-2-(N-methyl-1,2,3,6-tetrahydropyrid-4-yl)eth-1-yl]acetamide

2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(methoxycarbonyl)-2-(N-methylpiperidin-4-yl)eth-1-yl]acetamide

2-[2-(S orR)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(methoxycarbonyl)-2-(N-methylpiperidin-4-yl)eth-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(S)-[pyrrolidin-N-ylcarbonyl]-2-[4-(2-imidazolin-2-yl)phenyl]eth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(S)-(t-butoxycarbonyl)-3-methylbut-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(t-butoxycarbonyl)-3-methylprop-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(S)-(t-butoxycarbonyl)-2-(4-hydroxyphenyl)eth-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(t-butoxycarbonyl)-2-(phenyl)eth-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(S)-carboxamide-2-(indol-3-yl)eth-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-carboxamide-2-(phenyl)eth-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(S)-carboxamide-2-(S)-methylbut-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(S)-carboxamide-2-(phenyl)eth-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(S)-ethoxycarbonyleth-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(S)-1,3-dicarboxamideprop-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(N-cyclopropylpiperidin-4-yl)-1-(R)-(pyrrolidin-N-ylcarbonyl)eth-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(N-methyl-1,2,5,6-tetrahydropyrid-4-yl)-1(R)-(pyrrolidin-N-ylcarbonyl)eth-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(N-methylpiperidin-4-yl)-1-(R)-(pyrrolidin-N-ylcarbonyl)eth-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-cyanophenyl)-1-(R)-(pyrrolidin-N-ylcarbonyl)eth-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-cyanophenyl)-1-(S)-(pyrrolidin-N-ylcarbonyl)eth-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-hydroxyphenyl)-1-(S)-(methoxycarbonyl)eth-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-hydroxyphenyl)-1-(S)-(t-butoxycarbonyl)eth-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-hydroxyphenyl)-1-(R)-(methoxycarbonyl)eth-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(indol-3-yl)-1-(S)-(methoxycarbonyl)eth-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(indol-3-yl)-1-(R)-(methoxycarbonyl)eth-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(phenyl)-1-(S)-(pyrrolidin-N-ylcarbonyl)eth-1-yl]-N-methylacetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)-1-(R)-(pyrrolidin-N-ylcarbonyl)eth-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-phenyl-1-(S)-(methoxycarbonyl)eth-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(2-phenyl-1-(R)-carboxy-eth-1-yl)acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(α,α-dimethylglycine)piperidin-4-yl]eth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-[N-(α-aminoacetyl)piperidin-4-yl]eth-1-yl}acetamide

2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[4-(imidazolin-2-yl)phenyl]-1-(R)-(pyrrolidin-1-ylcarbonyl)eth-1-yl}acetamide

2-[2-(S orR)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[4-(imidazolin-2-yl)phenyl]-1-(R)-(pyrrolidin-1-ylcarbonyl)eth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[3-(dimethylamino)prop-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(3-t-butoxycarbonyl-1-methoxycarbonylprop-1-yl)acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-aminoacetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[4-(ethylaminoamidino)phenyl]eth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-methylcarboxamideacetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-cyanomethylacetamide

2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[(4-imidazolin-2-yl)phenyl]1-(R)-(pyrrolidin-N-ylcarbonyl)eth-1-yl}acetamide

2-[2-(S orR)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[(4-imidazolin-2-yl)phenyl]1-(R)-(pyrrolidin-N-ylcarbonyl)eth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(S)-methoxy]-N-methylacetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-methoxycarbonylphenylmethyl)]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-methoxycarbonylmethylacetamide

2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[(4-amidinophenyl]-1-(R)-(pyrrolidin-N-ylcarbonyl)eth-1-yl}acetamide

2-[2-(S orR)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[(4-amidinophenyl]-1-(R)-(pyrrolidin-N-ylcarbonyl)eth-1-yl}acetamide

2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(pyrrolidin-N-ylcarbonyl)-3-(guanadino)but-1-yl]acetamide

2-[2-(S orR)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(pyrrolidin-N-ylcarbonyl)-3-(guanadino)but-1-yl]acetamide

2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(pyrrolidin-N-ylcarbonyl)-5-amino-n-pent-1-yl]acetamide

2-[2-(S orR)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(pyrrolidin-N-ylcarbonyl)-5-amino-n-pent-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(pyrrolidin-N-ylcarbonyl)-4-(N′-t-butoxy-carbonyl)-guanadino-n-but-1-yl]acetamide

2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-pyrrolidin-N-ylcarbonyl-5-(N′-t-butoxy-carbonylamino)-n-pent-5-yl]acetamide

2-[2-(S orR)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-pyrrolidin-N-ylcarbonyl-5-(N′-t-butoxy-carbonylamino)-n-pent-5-yl]acetamide

2-[2-(S orR)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(pyrrolidin-N-ylcarbonyl)-4-amino-n-butyl]acetamide

2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(pyrrolidin-N-ylcarbonyl)-4-(N′-t-butoxy-carbonylamino)-n-but-1-yl]acetamide

2-[2-(S orR)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(pyrrolidin-N-ylcarbonyl)-4-(N′-t-butoxy-carbonylamino)-n-but-1-yl]acetamide

2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(pyrrolidin-N-ylcarbonyl)-2-(4-amidino)phenyl-eth-1-yl]acetamide

2-[2-(S orR)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(pyrrolidin-N-ylcarbonyl)-2-(4-amidino)phenyl-eth-1-yl]acetamide

2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(pyrrolidin-N-ylcarbonyl)-4-guanidino-but-1-yl]acetamide

2-[2-(S orR)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(pyrrolidin-N-ylcarbonyl)-4-guanidino-but-1-yl]acetamide

2-[2-(S,R)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-methylenecarbonyl-[4-(2-aminoethyl)]piperidin-1-yl]acetamide

2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(pyrrolidin-N-ylcarbonyl)-2-(4-iodophenyl)eth-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-methylenecarbonyl-{[4-(2-(N-t-butoxycarbonylamino)ethyl)piperidin-1-yl)}acetamide

2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(pyrrolidin-N-ylcarbonyl)-4-amino-n-butyl]acetamide

2-[2-(S orR)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(pyrrolidin-N-ylcarbonyl)-4-amino-n-butyl]acetamide

2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(pyrrolidin-N-ylcarbonyl)-5-(t-butoxy-carbonylamino)-pent-5-yl]acetamide

2-[2-(S orR)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(pyrrolidin-N-ylcarbonyl)-5-(t-butoxy-carbonylamino)-pent-5-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-methylenecarbonyl{[1-(pyridin-2-yl)]-4-piperazin-4-yl}acetamide

2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(pyrrolidin-N-ylcarbonyl)-5-amino-n-pent-1-yl]acetamide

2-[2-(S orR)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(pyrrolidin-N-ylcarbonyl)-5-amino-n-pent-1-yl]acetamide

2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(pyrrolidin-N-ylcarbonyl)-4-(t-butoxy-carbonylamino)-n-but-1-yl]acetamide

2-[2-(S orR)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(pyrrolidin-N-ylcarbonyl)-4-(t-butoxy-carbonylamino)-n-but-1-yl]acetamide

2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(pyrrolidin-N-ylcarbonyl)-2-(4-iodophenyl)-eth-1-yl]acetamide

2-[2-(S orR)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(pyrrolidin-N-ylcarbonyl)-2-(4-iodophenyl)-eth-1-yl]acetamide

2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[4-(pyrid-2-yl)phenyl]eth-1-yl}acetamide

2-[2-(S orR)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[4-(pyrid-2-yl)phenyl]eth-1-yl}acetamide

2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[4-(pyrid-2-yl)phenyl]eth-1-yl}acetamide

2-[2-(S orR)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[4-(pyrid-2-yl)phenyl]eth-1-yl}acetamide

2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R)-(pyrrolidin-N-ylcarbonyl)-2-[4-(pyrimidin-2-yl)phenyl]eth-1-yl}acetamide

2-[2-(S orR)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R)-(pyrrolidin-N-ylcarbonyl)-2-[4-(pyrimidin-2-yl)phenyl]eth-1-yl}acetamide

2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[4-(piperidin-2-yl)cyclohexyl]eth-1-yl}acetamide

2-[2-(S orR)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[4-(piperidin-2-yl)cyclohexyl]eth-1-yl}acetamide

2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[4-(N-methyl-1,2,3,6-tetrahydropyridin-6-yl)phenyl]eth-1-yl}acetamide

2-[2-(S orR)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[4-(N-methyl-1,2,3,6-tetrahydropyridin-6-yl)phenyl]eth-1-yl}acetamide

2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[4-(pyridin-4-yl)phenyl]eth-1-yl}acetamide

2-[2-(S orR)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[4-(pyridin-4-yl)phenyl]eth-1-yl}acetamide

2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[N-(phenyl)-piperidin-4-yl)]eth-1-yl}acetamide

2-[2-(S orR)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[N-(phenyl)-piperidin-4-yl)]eth-1-yl}acetamide

2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[N-(pyridin-4-yl)-piperidin-4-yl]eth-1-yl}acetamide

2-[2-(S orR)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[N-(pyridin-4-yl)-piperidin-4-yl]eth-1-yl}acetamide

2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[(N-methyl-1,2,5,6-tetrahydropyridin-4-yl)-phen-4-yl]eth-1-yl}acetamide

2-[2-(S orR)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[(N-methyl-1,2,5,6-tetrahydropyridin-4-yl)-phen-4-yl]eth-1-yl}acetamide

2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(pyrrolidin-N-ylcarbonyl)-2-(4-biphenyl)ethy-1-yl]acetamide

2-[2-(S orR)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(pyrrolidin-N-ylcarbonyl)-2-(4-biphenyl)eth-1-yl]acetamide

2-[2-(S orR)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[4-(N-t-butoxycarbonylpyrrol-2-yl)phenyl]eth-1-yl}acetamide

2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[4-(N-t-butoxycarbonylpyrrol-2-yl)phenyl]eth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(′,N′-dimethylaminocarbonyl)aminophen-1-yl]eth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(methylcarbonylmethylene)piperidin-4-y]eth-1-yl}acetamide

2-[2-(R,S)-1-(2,3-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(N′,N′-dimethylamino)eth-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(N′-morpholinocarbonyl)piperidin-4-yl]eth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-[(thiophen-2-yl)methylenecarbonyl]piperidin-4-yl]eth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(3,5-dimethyloxazol-4-ylcarbonyl)piperidin-4-yl]eth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[(N-furan-2-ylcarbonyl)piperidin-4-yl]eth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(3,5-dimethyloxazol-3-ylcarbonyl)piperidin-4-yl]eth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-2-[N-(5-methylpyrazol-3-ylcarbonyl)piperidin-4-yleth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(1-methyl-3-t-butylpyrazol-5-ylcarbonyl)piperidin-4-yl]eth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(4-methylthiadiazol-5-ylcarbonyl)piperidin-4-yl]eth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]-N-{2-[N-(chloromethylenecarbonyl)piperidin-4-yleth-1-yl}-acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(benzylcarbonyl)piperidin-4-yl]eth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(2-phenylethenylcarbonyl)piperidin-4-yl]eth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(methoxymethylenecarbonyl)piperidin-4-yl]eth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(pyrazin-2-ylcarbonyl)piperidin-4-yl]eth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(isoquinolin-3-ylcarbonyl)piperidin-4-yl]eth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(pyrrolidin-5-one-2-ylcarbonyl)piperidin-4-yl]eth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(N′-acetylpyrrolidin-2-ylcarbonyl)piperidin-4-yl]eth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(dichloromethylenecarbonyl)piperidin-4-yl]eth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(pyrazin-2-ylcarbonyl)amino]pheneth-1-yl}-acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(isoquinolin-2-ylcarbonyl)amino]pheneth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(N′-acetylpyrrolidin-2-ylcarbonyl)amino]pheneth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(1,2-benzothiadiazol-5-ylcarbonyl)amino]pheneth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(benzofuran-5-ylcarbonyl)amino]pheneth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(3-methylisoxazol-5-ylcarbonyl)amino]pheneth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(N-morpholinocarbonyl)amino]pheneth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(methoxyphen-3-ylcarbonyl)amino]pheneth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(thiophen-2-ylmethylenecarbonyl)amino]pheneth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(3,5-dimethylisoxazol-4-ylcarbonyl)amino]pheneth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(2-(pyrid-3-yl)ethylcarbonyl)amino]pheneth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(furan-2-ylcarbonyl)amino]pheneth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(isoxazol-5-ylcarbonyl)amino]pheneth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(3-methylpyrazol-5-ylcarbonyl)amino]pheneth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(1-methyl-3-t-butylpyrazol-5-ylcarbonyl)amino]pheneth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(4-methyl-1,2,3-thiadiazol-5-ylcarbonyl)amino]pheneth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(chloromethylenecarbonyl)amino]pheneth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(chlorophen-2-ylcarbonyl)amino]pheneth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(phenylcarbonyl)amino]pheneth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(pyrid-2-ylcarbonyl)amino]pheneth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(pyrid-4-ylcarbonyl)amino]pheneth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(2-phenylethenylcarbonyl)amino]pheneth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(fluorophen-2-ylcarbonyl)amino]pheneth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-etrahydroquinoxalin-2-yl]-N-{4-[N-(methoxymethylenecarbonyl)amino]pheneth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(dichloromethylenecarbonyl)amino]pheneth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(methylenedioxyphen-4-ylcarbonyl)amino]pheneth-1-yl}acetamide

2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-[(R)-(pyrrolidin-N-ylcarbonyl)]-2-[N-(methylpyrid-2-yl)phen-4-yl]eth-1-yl}acetamide

2-[2-(S orR)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-[(R)-(pyrrolidin-N-ylcarbonyl)]-2-[N-(methylpyrid-2-yl)phen-4-yl]eth-1-yl}acetamide

2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-[(R)-(pyrrolidin-N-ylcarbonyl)]-2-[N-(methylpyrid-4-yl)phen-4-yl]eth-1-yl}acetamide

2-[2-(S orR)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-[(R)-(pyrrolidin-N-ylcarbonyl)]-2-[N-(methylpyrid-4-yl)phen-4-yl]eth-1-yl}acetamide

2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-[(R)-(pyrrolidin-N-ylcarbonyl)]-2-[1-(piperidin-2-yl)phen-4-yl]eth-1-yl}acetamide

2-[2-(S orR)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-[(R)-(pyrrolidin-N-ylcarbonyl)]-2-[1-(piperidin-2-yl)phen-4-yl]eth-1-yl}acetamide

2-[2-(R or S)-1-(4-chloro,2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-methyl-N-{1-[(R)-pyrrolidin-N-ylcarbonyl)-2-[4-(N-methylpyrid-4-yl)phen-}acetamide

2-[2-(S orR)-1-(4-chloro-2,5-diethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-methyl-N-{1-[(R)-pyrrolidin-N-ylcarbonyl)-2-[4-(N-methylpyrid-4-yl)phen-1-yl)eth-1-yl]}acetamide

2-[2-(R,S)-1-(2,5-dimethyl-4-chlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[4-(pyridin-2-yl)-3-butyn-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[4-(pyrid-4-yl)but-3-yn-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(benzoimidazol-2-ylamino)eth-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[3-(benzoimidazol-2-ylamino)prop-1-yl]acetamide

and pharmaceutically acceptable salts thereof.

Further included within the scope of the compounds of this invention isthe following:

This invention also provides a pharmaceutical composition comprising apharmaceutically acceptable carrier and a therapeutically effectiveamount of a compound of Formula I or II (including mixtures thereof) ora pharmaceutically acceptable salt thereof to treat or palliate adversesymptoms in mammals which symptoms are mediated, at least in part, bythe presence of bradykinin.

This invention further provides a method for treating or palliatingadverse symptoms in a mammal associated with the presence or secretionof bradykinin in the mammal which comprises administering thereto atherapeutically effective amount of a compound Formula I or II(including mixtures thereof) or a pharmaceutically acceptable saltthereof or, as is more generally the case, administering apharmaceutical composition as described above.

This invention also provides a method for treating or ameliorating pain,hyperalgesia, hyperthermia and/or edema in a mammal which is associatedwith the release of bradykinin in the mammal which comprisesadministering to the mammal a therapeutically effective amount of acompound Formula I or II (including mixtures thereof) or apharmaceutically acceptable salt thereof or, as is more generally thecase, administering a pharmaceutical composition as described above.

This invention still further provides a method for treating orameliorating adverse symptoms in a mammal associated with the release ofbradykinin relative to spinal cord injuries, neuropathic pain, backpain, burns, perioperative pain, migraine, shock, central nervous systeminjury, asthma, rhinitis, premature labor, inflammatory arthritis, orinflammatory bowel disease which comprises administering to the mammal atherapeutically effective amount of a compound Formula I or II(including mixtures thereof) or a pharmaceutically acceptable saltthereof or, as is more generally the case, administering apharmaceutical composition as described above.

This invention also provides intermediates and processes forsynthesizing the compounds of Formulas I-III.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

As noted above, this invention is directed, in part, to certain1,2,3,4-tetrahydrosulfonylquinoxalone acetamide derivatives representedby Formula I above. In turn, the compounds of Formula I can also berepresented by the following subgeneric Formulas I(a) through I(i):

wherein Y′ is ═O or ═S; Y′ is —O— or —S— and R⁷ is as defined above but,in Formula I(c), R⁷ is not hydrogen; and n, R, R¹, R², R³ and R⁸ are asdefined above.

In terms of preferred substituents, the preferred compounds of Formula Iof this invention in terms of potency, duration of action manufactureease and/or ease of administration are compounds having at least one ofthe following preferred substituents.

In one preferred embodiment, p is one, R⁷ is hydrogen and n is zero.

In another preferred embodiment, p is one, R⁷ is hydrogen, n is one ortwo and each of R³ is independently hydrogen, alkyl or halo morepreferably chloro or fluoro.

In still another preferred embodiment, R is a substituted phenyl,naphthyl, or substituted naphthyl group. More preferably, R is4-chloro-2,5-dimethylphenyl, or 2,3-dichlorophenyl.

Preferably, W is nitrogen and one and only one of R¹ and R² is hydrogenor R¹ and R² together with the nitrogen atom to which they are joinedform a heteroaryl, substituted heteroaryl, heterocyclic or substitutedheterocyclic group.

Definitions

Unless otherwise expressly defined with respect to a specific occurrenceof the term, the following terms as used herein shall have the followingmeanings regardless of whether capitalized or not.

The term 1,2,3,4-tetrahydroquinoxaline refers to the ring structure setforth below in which positions 1-4 are numbered according to convention.

The term “alkyl” refers to alkyl groups having from 1 to 10 carbon atomsand more preferably 1 to 6 carbon atoms and includes both straight chainand branched chain alkyl groups. This term is exemplified by groups suchas methyl, t-butyl, n-heptyl, octyl and the like. The term “alkylene”refers to a divalent alkyl group.

The term “substituted alkyl” refers to an alkyl group, of from 1 to 10carbon atoms, more preferably, 1 to 6 carbon atoms, having from 1 to 5substituents, preferably 1 to 3 substituents, independently selectedfrom the group consisting of alkoxy, substituted alkoxy, acyl,acylamino, thiocarbonylamino, acyloxy, amino, substituted amino,amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl,aryloxy, substituted aryloxy, aryloxylaryl, substituted aryloxyaryl,cyano, halogen, hydroxyl, nitro, oxo, thioxo, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl,thioaryl, substituted thioaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂—OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl,—NRS(O)₂—NR-aryl, —NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic, and—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl. Theterm “substituted alkylene” refers to a divalent substituted alkyl.

“Lower alkyl” and “substituted lower alkyl” are defined as above,wherein the number of carbon atoms is from 1 to 5, more preferably, 1-3carbon atoms.

“Alkoxy” refers to the group “alkyl-O—” which includes, by way ofexample, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy,sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.

“Substituted alkoxy” refers to the group “substituted alkyl-O—”.

“Acyl” refers to the groups H—C(O)—, alkyl-C(O)—, substitutedalkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, alkynyl-C(O)—,substituted alkynyl-C(O)—, cycloalkyl-C(O)—, substitutedcycloalkyl-C(O)—, aryl-C(O)—, substituted aryl-C(O)—, heteroaryl-C(O)—,substituted heteroaryl-C(O), heterocyclic-C(O)—, and substitutedheterocyclic-C(O)— provided that a nitrogen atom of the heterocyclic orsubstituted heterocyclic is not bound to the —C(O)— group wherein alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic are as defined herein.

“Amino” refers to the group —NH₂.

“Substituted amino” refers to the group —NRR, where each R group isindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-alkenyl,—SO₂-substituted alkenyl, —SO₂-cycloalkyl, —SO₂-substituted cycloalkyl,—SO₂-aryl, —SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substitutedheteroaryl, —SO₂-heterocyclic, —SO₂-substituted heterocyclic, providedthat both R groups are not hydrogen; or the R groups can be joinedtogether with the nitrogen atom to form a heterocyclic or substitutedheterocyclic ring.

The term “acylamino” or as a prefix “carbamoyl” or “carboxamide” or“substituted carbamoyl” or “substituted carboxamide” refers to the group—C(O)NRR where each R is independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl,cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic and where each R is joined toform together with the nitrogen atom a heterocyclic or substitutedheterocyclic wherein alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic and substituted heterocyclic are as defined herein.

“Thiocarbonylamino” or as a prefix “thiocarbamoyl” “thiocarboxamide” or“substituted thiocarbamoyl” or “substituted thiocarboxamide” refers tothe group —C(S)NRR where each R is independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl,cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic and where each R is joined toform, together with the nitrogen atom a heterocyclic or substitutedheterocyclic wherein alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic and substituted heterocyclic are as defined herein.

“Acyloxy” refers to the groups acyl-O— where acyl is as defined herein.

“Alkenyl” refers to alkenyl group having from 2 to 10 carbon atoms andmore preferably 2 to 6 carbon atoms and having at least 1 and preferablyfrom 1-2 sites of alkenyl unsaturation. The term “alkenylene” refers toa divalent alkenyl group.

“Substituted alkenyl” refers to alkenyl groups having from 1 to 5substituents, preferably 1 to 3 substituents, independently selectedfrom the group of substituents defined for substituted alkyl. The term“substituted alkenylene” refers to a divalent substituted alkenyl group.

“Alkynyl” refers to alkynyl group having from 2 to 10 carbon atoms andmore preferably 3 to 6 carbon atoms and having at least 1 and preferablyfrom 1-2 sites of alkynyl unsaturation. The term “alkynylene” refer to adivalent substituted alkynylene group.

“Substituted alkynyl” refers to alkynyl groups having from 1 to 5,preferably 1 to 3 substituents, selected from the same group ofsubstituents as defined for substituted alkyl. The term “substitutedalkynylene” refers to as divalent substituted alkynylene group.

“Amidino” refers to the group H₂NC(═NH)— and the term “alkylamidino”refers to compounds having 1 to 3 alkyl groups (e.g., alkylHNC(═NH)—)where alkyl is as defined herein.

“Thioamidino” refers to the group RSC(═NH)— where R is hydrogen or alkylwhere alkyl is as defined herein.

“Aminoacyl” refers to the groups —NRC(O)alkyl, —NRC(O)substituted alkyl,—NRC(O)cycloalkyl, —NRC(O)substituted cycloalkyl, —NRC(O)alkenyl,—NRC(O)substituted alkenyl, —NRC(O)alkynyl, —NRC(O)substituted alkynyl,—NRC(O)aryl, —NRC(O)substituted aryl, —NRC(O)heteroaryl,—NRC(O)substituted heteroaryl, —NRC(O)heterocyclic, and—NRC(O)substituted heterocyclic where R is hydrogen or alkyl and whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are defined herein.

“Aminocarbonyloxy” refers to the groups —NRC(O)O-alkyl,—NRC(O)O-substituted alkyl, —NRC(O)O-alkenyl, —NRC(O)O-substitutedalkenyl, —NRC(O)O-alkynyl, —NRC(O)O-substituted alkynyl,—NRC(O)O-cycloalkyl, —NRC(O)O-substituted cycloalkyl, —NRC(O)O-aryl,—NRC(O)O-substituted aryl, —NRC(O)O-heteroaryl, —NRC(O)O-substitutedheteroaryl, —NRC(O)O-heterocyclic, and —NRC(O)O-substituted heterocyclicwhere R is hydrogen or alkyl and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Oxycarbonylamino” or as a prefix “carbamoyloxy” or “substitutedcarbamoyloxy” refers to the groups —OC(O)NRR where each R isindependently hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, and substituted heterocyclic or where each R is joined toform, together with the nitrogen atom a heterocyclic or substitutedheterocyclic and wherein alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic and substituted heterocyclic are as defined herein.

“Oxythiocarbonylamino” refers to the groups —OC(S)NRR where each R isindependently hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, and substituted heterocyclic or where each R is joined toform, together with the nitrogen atom a heterocyclic or substitutedheterocyclic and wherein alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic and substituted heterocyclic are as defined herein.

“Aminocarbonylamino” refers to the group —NR′C(O)NR″R″ where R′ isselected from the group consisting of hydrogen and alkyl and each R″ isindependently selected from hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, aryl, substitutedaryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic or where each R″is joined to form together with the nitrogen atom a heterocyclic orsubstituted heterocyclic and the like and wherein alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic are asdefined herein.

“Aminothiocarbonylamino” refers to the group —NR′C(S)NR″R″ where R′ isselected from the group consisting of hydrogen and alkyl and each R″ isindependently selected from hydrogen, alkyl, substituted alky, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, aryl, substitutedaryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic or where each R″is joined to form together with the nitrogen atom a heterocyclic orsubstituted heterocyclic, and the like and wherein alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic are asdefined herein.

“Aryl” or “Ar” refers to an aromatic carbocyclic group of from 6 to 14carbon atoms having a single ring (e.g., phenyl) or multiple condensedrings (e.g., naphthyl or anthryl) which condensed rings may or may notbe aromatic (e.g., 2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-one-7-yl,and the like). Preferred aryls include phenyl and naphthyl.

“Substituted aryl” refers to aryl groups which are substituted with from1 to 4, preferably 1-3, substituents selected from the group consistingof hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl,substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, amidino, alkylamidino,thioamidino, amino, substituted amino, aminoacyl, aminocarbonyloxy,aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl,aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy,heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substitutedheterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl, substitutedthioaryl, thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl,substituted thiocycloalkyl, thioheterocyclic, substitutedthioheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino,guanidinosulfone, halo, nitro, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic, oxycarbonylamino,oxythiocarbonylamino, —S(O)₂-alkyl, —S(O)₂-substituted alkyl,—S(O)₂-cycloalkyl, —S(O)₂-substituted cycloalkyl, —S(O)₂-alkenyl,—S(O)₂-substituted alkenyl, —S(O)₂-aryl, —S(O)₂-substituted aryl,—S(O)₂-heteroaryl, —S(O)₂-substituted heteroaryl, —S(O)₂-heterocyclic,—S(O)₂-substituted heterocyclic, —OS(O)₂-alkyl, —OS(O)₂-substitutedalkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl,wherein each of the terms is as defined herein.

“Aryloxy” refers to the group aryl-O— which includes, by way of example,phenoxy, naphthoxy, and the like wherein aryl is as defined herein.

“Substituted aryloxy” refers to substituted aryl-O— groups wheresubstituted aryl is as defined herein.

“Aryloxyaryl” refers to the group -aryl-O-aryl where aryl is as definedherein.

“Substituted aryloxyaryl” refers to aryloxyaryl groups substituted withfrom 1 to 4, preferably 1 to 3 substituents on either or both aryl ringsindependently selected from the same group consisting of substituents asdefined for substituted aryl.

“Cycloalkyl” refers to cyclic alkyl groups of from 3 to 10 carbon atomshaving a single or multiple cyclic rings including, by way of example,cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, adamantanyl, and thelike.

“Cycloalkenyl” refers to cyclic alkenyl groups of from 3 to 8 carbonatoms having single or multiple unsaturation but which are not aromatic.

“Substituted cycloalkyl” and “substituted cycloalkenyl” refer to acycloalkyl and cycloalkenyl groups, as defined herein, having from 1 to5, preferably 1-3 substituents independently selected from the samegroup of substituents as defined for substituted alkyl.

“Cycloalkoxy” refers to —O-cycloalkyl groups where cycloalkyl is asdefined herein.

“Substituted cycloalkoxy” refers to —O-substituted cycloalkyl groupswhere substituted cycloalkyl is as defined herein.

“Guanidino” or “substituted guanidino” refers to the groups—NR′C(═NR′)NR″R″ where each R′ is independently hydrogen or alkyl andeach R″ is independently selected from the group consisting of hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, cycloalkyl, heteroaryl,substituted heteroaryl, heterocyclic, and substituted heterocyclic andwherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, alkoxy,substituted alkoxy, acyloxy, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic are asdefined herein.

“Guanidinosulfone” refers to the groups —NR′C(═NR′)NR′SO₂-alkyl,—NR′C(═NR′)NR′SO₂-substituted alkyl, —NR′C(═NR′)NR′SO₂-alkenyl,—NR′C(═NR′)NR′SO₂-substituted alkenyl, —NR′C(═NR′)NR′SO₂-alkynyl,—NR′C(═NR′)NR′SO₂-substituted alkynyl, —NR′C(═NR′)NR′SO₂-aryl,—NR′C(═NR′)NR′SO₂-substituted aryl, —NR′C(═NR′)NR′SO₂-cycloalkyl,—NR′C(═NR′)NR′SO₂-substituted cycloalkyl, —NR′C(═NR′)NR′SO₂-heteroaryl,—NR′C(═NR′)NR′SO₂-substituted heteroaryl,—NR′C(═NR′)NR′SO₂-heterocyclic, and —NR′C(═NR′)NR′SO₂-substitutedheterocyclic where each R′ is independently hydrogen and alkyl andwherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Halo” or “halogen” refers to fluoro, chloro, bromo and iodo andpreferably is either chloro or fluoro.

“Heteroaryl” refers to an aromatic group of from 1 to 10 ring carbonatoms and 1 to 4 ring heteroatoms selected from oxygen, nitrogen andsulfur within the ring. Such heteroaryl groups can have a single ring(e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinylor benzothienyl). Preferred heteroaryls include pyridyl, pyrrolyl,indolyl and furyl.

“Substituted heteroaryl” refers to heteroaryl groups, as defined above,which are substituted with from 1 to 3 substituents independentlyelected from the same group of substituents as defined for “substitutedaryl”.

“Heteroaryloxy” refers to the group —O-heteroaryl and “substitutedheteroaryloxy” refers to the group —O-substituted heteroaryl whereheteroaryl and substituted heteroaryl are as defined above.

“Heterocycle,” “heterocyclyl” or “heterocyclic” refers to a saturated orunsaturated group having a single ring or multiple condensed rings, from1 to 10 ring carbon atoms and from 1 to 4 ring hetero atoms selectedfrom nitrogen, sulfur or oxygen within the ring wherein, in fused ringsystems, one or more of the rings can be aryl or heteroaryl.

“Saturated heterocyclic” refers to heterocycles of single or multiplecondensed rings lacking unsaturation in any ring (e.g., carbon to carbonunsaturation, carbon to nitrogen unsaturation, nitrogen to nitrogenunsaturation, and the like).

“Unsaturated heterocyclic” refers to non-aromatic heterocycles of singleor multiple condensed rings having unsaturation in any ring (e.g.,carbon to carbon unsaturation, carbon to nitrogen unsaturation, nitrogento nitrogen unsaturation, and the like).

“Substituted heterocyclic” refers to heterocycle groups, as definedabove, which are substituted with from 1 to 3 substituents independentlyselected from the group consisting of oxo (═O), thioxo (═S), plus thesame group of substituents as defined for substituted aryl.

Examples of heterocycles and heteroaryls include, but are not limitedto, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole,indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine,naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine,carbazole, carboline, phenanthridine, acridine, phenanthroline,isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,imidazolidine, imidazoline, piperidine, piperazine, indoline,phthalimide, 1,2,3,4-tetrahydro-isoquinoline,4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene,benzo[b]thiophene, morpholino, thiomorpholino, piperidinyl, pyrrolidine,tetrahydrofuranyl, and the like.

“Substituted saturated heterocyclic” refers to substituted heterocycles,as defined above, of single or multiple condensed rings lackingunsaturation in any ring (e.g., carbon to carbon unsaturation, carbon tonitrogen unsaturation, nitrogen to nitrogen unsaturation, and the like).

“Substituted unsaturated heterocyclic” refers to non-aromaticsubstituted heterocycles of single or multiple condensed rings havingunsaturation in any ring (e.g., carbon to carbon unsaturation, carbon tonitrogen unsaturation, nitrogen to nitrogen unsaturation, and the like).

“Heterocyclyloxy” refers to the group —O-heterocyclic and “substitutedheterocyclyloxy” refers to the group —O-substituted heterocyclic whereheterocyclic and substituted heterocyclyoxy are as defined above.

“Thiol” refers to the group —SH.

“Thioalkyl” refers to the groups —S-alkyl where alkyl is as definedabove.

“Substituted thioalkyl” refers to the group —S-substituted alkyl wheresubstituted alkyl is as defined above.

“Thiocycloalkyl” refers to the groups —S-cycloalkyl where cycloalkyl isas defined above.

“Substituted thiocycloalkyl” refers to the group —S-substitutedcycloalkyl where substituted cycloalkyl is as defined above.

“Thioaryl” refers to the group —S-aryl and “substituted thioaryl” refersto the group —S-substituted aryl where aryl and substituted aryl are asdefined above.

“Thioheteroaryl” refers to the group —S-heteroaryl and “substitutedthioheteroaryl” refers to the group —S-substituted heteroaryl whereheteroaryl and substituted heteroaryl are as defined above.

“Thioheterocyclic” refers to the group —S-heterocyclic and “substitutedthioheterocyclic” refers to the group —S-substituted heterocyclic whereheterocyclic and substituted heterocyclic are as defined above.

“Pharmaceutically acceptable salt” refers to pharmaceutically acceptablesalts of a compound of Formula I which salts are derived from a varietyof organic and inorganic counter ions well known in the art and include,by way of example only, sodium, potassium, calcium, magnesium, ammonium,tetraalkylammonium, and the like; and when the molecule contains a basicfunctionality, salts of organic or inorganic acids, such ashydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate,oxalate and the like.

Compound Preparation

The compounds of this invention can be prepared from readily availablestarting materials using the following general methods and procedures.It will be appreciated that where typical or preferred processconditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization procedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. Suitableprotecting groups for various functional groups as well as suitableconditions for protecting and deprotecting particular functional groupsare well known in the art. For example, numerous protecting groups aredescribed in T. W. Greene and G. M. Wuts, Protecting Groups in OrganicSynthesis, Second Edition, Wiley, N.Y., 1991, and references citedtherein.

Furthermore, the compounds of this invention will typically contain oneor more chiral centers. Accordingly, if desired, such compounds can beprepared or isolated as pure stereoisomers, i.e., as individualenantiomers or diastereomers, or as stereoisomer-enriched mixtures. Allsuch stereoisomers (and enriched mixtures) are included within the scopeof this invention, unless otherwise indicated. Pure stereoisomers (orenriched mixtures) may be prepared using, for example, optically activestarting materials or stereoselective reagents well-known in the art.Alternatively, racemic mixtures of such compounds can be separatedusing, for example, chiral column chromatography, chiral resolvingagents and the like.

In one embodiment, the compounds of Formula I, wherein W is N and R¹ andR² are H, can be prepared via the following reaction scheme, Scheme 1:

wherein R, R³, and R⁷ are as defined herein above.

In Scheme 1, an appropriately substituted 1,2-diaminobenzene compound(600) is condensed with at least a stoichiometric equivalent, andpreferably an excess of maleimide (601) to provide a quinoxaloneacetamide intermediate (602).

This reaction is typically performed in an inert organic solvent, forexample, methanol, water, and the like, and is typically conducted attemperatures in the range of 20 to 100° C. until the reaction iscomplete, which typically occurs within 1 to 2 hours. The resultingproduct can be recovered by conventional methods, such aschromatography, filtration, crystallization, and the like, or can beused in the next step without purification or isolation.

The quinoxalone acetamide intermediate (602) can then be sulfonated withthe desired sulfonyl chloride (RSO₂Cl) to yield the sulfonatedquinoxalone acetamide (603). The sulfonation is typically effected bycontacting the quinoxalone acetamide intermediate (602) with about astoichiometric amount, or slight excess, of the desired sulfonylchloride in the presence of a scavenger base, such as pyridine, and thelike in an inert diluent. The reaction is typically conducted attemperatures in the range of about 0° C. to about room temperature for aperiod of time to effect sulfonation, which is typically 2 to 12 hours.Suitable inert solvents which can be used include, dichloromethane, andthe like. The resulting product can be recovered by conventionalmethods, such as chromatography, filtration, crystallization, and thelike, or can be used in the next step without purification or isolation.

The compounds of Formula I, wherein W is N, O, or S, can also beprepared as illustrated below in Scheme 2.

wherein R, R¹, R², R³, and R⁷ are as defined herein above and X′ is O orS.

In Scheme 2, an appropriately substituted 1,2-diaminobenzene compound(600) is condensed with at least a stoichiometric equivalent, andpreferably a slight excess of maleic anhydride (601(a)) to provide aquinoxalone acetic acid intermediate (605). This reaction is typicallyperformed in an inert organic solvent, for example, methanol, water, andthe like, and is typically conducted at temperatures in the range of 20to 100° C. until the reaction is complete, which typically occurs within1 to 2 hours. The resulting product can be recovered by conventionalmethods, such as chromatography, filtration, crystallization, and thelike, or can be used in the next step without purification or isolation.

Compounds of Formula I (where W is N) are prepared by reaction of thecarboxyl group of the quinoxalone acetic acid intermediate (605) with aslight excess of a primary or secondary amine or nitrogen heterocycle(606) under reactive conditions, preferably in the presence of an inertorganic solvent, a coupling agent and an organic base using amidationmethods well known in the art. This reaction is preferably conductedusing an excess of an amine (606) (about from 0.99 to 1.2 molarequivalents per mole of quinoxalone acetic acid) at temperatures in therange of about −20° C. to room temperature. The reaction is continueduntil completion, which typically occurs in 2 to 12 hours. Suitableinert organic solvents which can be used include, for example,N,N-dimethylformamide, acetonitrile, dichloromethane, and the like.Suitable coupling agents which may be used include1-hydroxybenzotriazole hydrate (HOBT) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI),diphenylphosphoryl azide (DPPA), and the like. Suitable organic basesinclude triethylamine (TEA), pyridine, N-methyl morpholine,diisopropylethyl amine (DIEA), and the like. The resulting product canbe recovered by conventional methods, such as chromatography,filtration, crystallization, and the like, or can be used in the nextstep without purification or isolation.

The quinoxalone acetamide compound (607) is then sulfonated with thedesired sulfonyl chloride RSO₂Cl, as described above, to yield thesulfonated quinoxalone acetamide (604).

For compounds of Formula I wherein W is O or S, the carboxyl group ofthe quinoxalone acetic acid intermediate (605) is esterified orthioesterified by contacting the quinoxalone acetic acid intermediate(605) with an appropriate alcohol or thiol (HX′R¹ wherein X′ is O or S).The esterification reaction may be catalyzed by H⁺. Thethioesterification is typically performed in an inert organic solvent,for example, pyridine, and is typically conducted with a stoichiometricamount of a dehydration agent, chlorinating agent, or activating agent,such as POCl₃. The reaction is typically conducted at temperatures inthe range of −20° C. to −10° C. until reaction completion, whichtypically occurs in 1 to 3 hours. The resulting intermediate is thensulfonated with the desired sulfonyl chloride RSO₂Cl, as describedabove, to yield the sulfonated quinoxalone ester or thioester (608(a)).Alternatively, for compounds where W is O, esterification can beachieved by reaction of the sulfonated carboxylic acid with alkyl iodidein a suitable solvent such as DMF in the presence of weak base such aspotassium carbonate wherein the reaction is maintained at about roomtemperature or by reaction with the alkyl halide in acetone maintainedat reflux.

Alternatively, the sulfonation andtransesterification/transthioesterification steps can be reversed suchthat the sulfonation is performed prior to the transesterification ortransthioesterification.

In another embodiment for compounds of Formula I where W is N, thesulfonation and amidation steps of Scheme 2 can be reversed.Specifically, as illustrated in Scheme 3 below, reaction of a sulfonatedquinoxalone acetic acid intermediate (608), with a primary or secondaryamine provides for the sulfonated quinoxalone acetamide (604).

wherein R, R¹, R², R³, and R⁷ are as defined herein above.

Specifically in this embodiment, a sulfonated quinoxalone acetic acidintermediate (608) (prepared by sulfonation of intermediate 605 in themanner described above) is contacted with a primary or secondary amineor nitrogen heterocycle (606) under reactive conditions, preferably inan inert organic solvent, in the presence of a coupling agent and anorganic base to yield the sulfonated quinoxalone acetamide (604). Theresulting product can be recovered by conventional methods, such aschromatography, filtration, crystallization, and the like, or can beused in the next step without purification or isolation. The conditionsfor this coupling reaction to provide the amide are as described abovefor Scheme 2.

In yet another embodiment, the quinoxalone acetic acid intermediate(605) can be prepared by hydrolysis of amide (602) using conditions wellknown in the art and then sulfonating as above to provide for thesulfonated quinoxalone acetic acid intermediate (608) which reactionscheme is illustrated below in Scheme 4.

wherein R, R³, and R⁷ are as defined herein above.

The first step of this process is typically effected by hydrolyzing thequinoxalone acetamide compound (602) in a suitable solvent such as anaqueous solution in the presence of a base to promote hydrolysis (10%sodium hydroxide). This reaction is typically conducted at elevatedtemperatures of about 50 to 100° C., and more preferably at reflux inthe reaction system used. The reaction is continued until completion,which typically occurs in about 1 to 5 hours. Suitable bases includeNaOH, LiOH, and the like. After hydrolysis of the amide yielding thecarboxylate, the quinoxalone acetic acid intermediate (605) may beyielded by contact with an acid, such as HCl, and the like. Theresulting product can be recovered by conventional methods, such aschromatography, filtration, crystallization, and the like, or can beused in the next step without purification or isolation.

The quinoxalone acetic acid intermediate (605) may then be sulfonatedwith the desired RSO₂Cl, as described above, to yield the sulfonatedquinoxalone acetic acid intermediate (608). The process illustrated inScheme 4 is, however, not preferred.

In still another embodiment, the quinoxalone acetic acid intermediate(605) can also be prepared as illustrated below in Scheme 5. Thisalternative embodiment to prepare the quinoxalone acetic acidintermediate (605) is useful for providing an approximately 50/50mixture of R and S isomers.

wherein R³ and R⁷ are as defined herein above and R⁶⁰ is preferablylower alky.

In Scheme 5, an optionally substituted 1,2-diaminobenzene compound (600)is condensed with a stoichiometric amount or a slight excess of adialkyl ester of 2-ketosuccinic acid (e.g. diethyl 2-keto succinate)(609) in an inert organic solvent, for example, dichloromethane,methanol, and the like, to yield an unsaturated quinoxalone esterintermediate (610). This reaction is typically conducted at or near roomtemperature. The reaction is continued until completion, which typicallyoccurs in 10 minutes to 1 hour. The resulting product can be recoveredby conventional methods, such as chromatography, filtration,crystallization, and the like, or can be used in the next step withoutpurification or isolation.

The unsaturated side chain of the quinoxalone ester intermediate (610)is then reduced to yield a quinoxalone ester (611). The reductionreaction may be conveniently effected by contacting the unsaturatedquinoxalone ester intermediate (610) with a stoichiometric amount of asuitable reducing agent, such as sodium cyanoborohydride, and the like.The reduction reaction is typically conducted in a polar organicsolvent, for example a THF and acetic acid mixture, methanol and aceticacid, and the like. This reaction is typically conducted at or near roomtemperature. The reaction is continued until completion, which typicallyoccurs in 10 min. to 2 hours. The resulting product can be recovered byconventional methods, such as chromatography, filtration,crystallization, and the like, or can be used in the next step withoutpurification or isolation.

In the next step, the quinoxalone ester (611) is hydrolyzed to yield thecorresponding quinoxalone acetic acid intermediate (605). This reactionmay be conveniently effected by contacting the quinoxalone ester (611)with a strong base, for example, lithium hydroxide monohydrate or sodiumhydroxide, in a suitable solvent. When lithium hydroxide monohydrate isused, the reaction is typically conducted at about 0° C. for about 10min to 6 hours in a suitable solvent, e.g., mixtures of tetrahydrofuranand water. The resulting sodium or lithium salt can be converted tocarboxylic acid form (—COOH) by contact with a dilute mineral acid,typically dilute aqueous hydrochloric acid. If desired, the R,S isomersformed can be separated by conventional techniques such as chiral columnchromatography, chiral resolving agents, and the like.

The quinoxalone acetic acid intermediate (605(a)), wherein R⁷ is H, mayalso be prepared as illustrated below in Scheme 6. This reaction schemeis useful for introducing chirality and thus providing purestereoisomers.

wherein R³ is as defined herein above and R⁶⁰ is lower alkyl (where *represents the chiral center).

In the first step of this process, an appropriately substituted1,2-fluoronitrobenzene (612) may be coupled with aspartic acid (613)yielding the diacid, and this may be followed by treatment with a loweralkyl iodide, typically methyl iodide, to yield the diester intermediate(614). When the aspartic acid reagent (613) is optically active, a purestereoisomer ester intermediate (614) is formed. The coupling reactionis typically conducted using stoichiometric amounts of reagents (612)and (613), or a modest stoichiometric excess of reactant (612), and aweak base e.g., sodium carbonate, in a suitable solvent, e.g., mixturesof methanol and water. The coupling reaction is typically conducted attemperatures in the range of 80 to 130° C. The coupling reaction iscontinued until completion, which typically occurs in 1 to 12 hours.

The ester intermediate (614) may be reduced and cyclized to thequinoxalone ester (611) by contact with hydrogen in the presence of anoble metal catalyst, e.g., platinum, in an inert organic solvent, e.g.,methanol. This reaction is typically conducted at temperatures in therange of 20 to 30° C., and pressures of about from 30 to 60 psi forabout from 3 to 12 hours. The resulting product can be recovered byconventional methods, such as chromatography, filtration,crystallization, and the like, or can be used in the next step withoutpurification or isolation.

In the next step, the ester group of the quinoxalone ester (611) ishydrolyzed to provide for the quinoxalone acetic acid intermediate (605)as described above for Scheme 5. If optically active starting materials(i.e., aspartic acid) are used, the resulting product (605) is isolatedas a pure stereoisomer. To ensure retention of optical center, no morethan about 1.05 equivalents and preferably from 0.99 to 1.00 equivalentsof base should be used during hydrolysis. In any event, the quinoxaloneacetic acid intermediate (605) is then converted to compounds of thisinvention in the manner described above.

In another embodiment, compounds of Formula I in which W is N and one ofR¹ and R² is H and the other is 2-(pyrid-4-yl)eth-1-yl or2-(piperidin-4-yl)eth-1-yl can be prepared as illustrated below inScheme 7.

wherein R, R³, and R⁷ are as defined herein above.

In the first step of this process, a quinoxalone acetic acidintermediate (605) is contacted with 4-(2-aminoethyl)pyridine underreactive conditions, preferably in an inert organic solvent in thepresence of a coupling agent and an organic base to yield thequinoxalone 2-(pyrid-4-yl)eth-1-yl amide derivative (615). Theconditions for this coupling reaction to provide the amide (615) are asdescribed above for Scheme 2. The resulting product can be recovered byconventional methods, such as chromatography, filtration,crystallization, and the like, or can be used in the next step withoutpurification or isolation.

The quinoxalone 2-(pyrid-4-yl)eth-1-yl amide derivative (615) is thensulfonated with the desired RSO₂Cl, as described above, to yield thesulfonated quinoxalone amide derivative (616). The resulting product canbe recovered by conventional methods, such as chromatography,filtration, crystallization, and the like, or can be used in the nextstep without purification or isolation.

As an optional step, the pyridine ring can be hydrogenated to yield thequinoxalone 2-(piperidin-4-yl)eth-1-yl amide derivative (617) by contactwith hydrogen in the presence of a noble metal catalyst, e.g., platinum,in an organic solvent, e.g., acetic acid. This reaction is typicallyconducted at temperatures in the range of 20 to 30° C., and pressures ofabout from 30 to 60 psi for 1 to 12 hours.

The compounds of Formula I where W is nitrogen and one of R¹ and R² is Hand the other is 2-(anilin-4-yl)eth-1-yl can be prepared as illustratedbelow in Scheme 8.

wherein R, R³, and R⁷ are as defined herein above.

Specifically, a sulfonated quinoxalone acetic acid intermediate (608) iscontacted with a 4-(2-aminoethyl)aniline (618) under reactiveconditions, preferably in an inert organic solvent in the presence of acoupling agent and an organic base to yield the quinoxalone2-(anilin-4-yl)eth-1-yl amide derivative (622). The conditions for thiscoupling reaction to provide the amide are as described above for Scheme2. The resulting product can be recovered by conventional methods, suchas chromatography, filtration, crystallization, and the like, or can beused in the next step without purification or isolation.

In the above reaction, the basicity of the aliphatic amine provides avehicle for the direct reaction with the aliphatic amine without thenecessity to block the aniline amine group. Contrarily, when amidationof the quinoxalone acetic acid intermediate (605) is conducted using apolyamine, e.g., a diamine, having two or more similarly reactive aminogroups, the use of blocking groups to provide for a single reactiveamino functionality will be necessary. Suitable conditions fordifferentially protecting and deprotecting amines on a polyamine arewell known in the art.

The sulfonated quinoxalone 2-(piper-4-yl)eth-1-yl amide derivative (617)and the sulfonated 2-(anilin-4-yl)eth-1-yl quinoxalone amide derivative(622) may be further derivatized as illustrated below in Scheme 9.

wherein R, R³, and R⁷ are as defined herein above and R¹⁰⁰ is selectedfrom the group consisting of alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, heterocycle, substituted heterocycle, aryl,substituted aryl, heteroaryl, and substituted heteroaryl.

In this process, aniline intermediate (622) or piperidine intermediate(617) is acylated with an acid chloride having the desired substitutentR¹⁰⁰ (623) in the presence of an organic base, such asdiisopropylethylamine (DIEA). This reaction is typically conducted in aninert organic solvent, such as dichloromethane, dioxane, and the like.The reaction is preferably conducted at room temperature for 1 to 12hours. If conversion is incomplete, an organic base (e.g., triethylamine(TEA)) may be added to assist in driving the reaction to completion.

In some instances generation of the acid chloride from the carboxylicacid may be necessary prior to the acylation step. This conversion canbe accomplished by dissolving the carboxylic acid in an inert organicsolvent (e.g., dichloromethane, dioxane, and the like) adding oxalylchloride plus a catalytic amount of N,N-dimethylformamide and shaking.This conversion can be conducted conveniently at room temperature for 2to 5 hours.

The compounds of Formula I, wherein Y and R⁷ together with the carbonatom and nitrogen atom to which they are joined forms an optionallysubstituted fused heteroaryl or an optionally substituted fusedsaturated or unsaturated heterocyclic structure, can be prepared asillustrated below in Scheme 10.

wherein R, R¹, R², and R³ are as defined herein above and R⁶⁰ is loweralkyl.

In the first step of this process, an appropriately substituted1,2-fluoronitrobenzene (612) is coupled with an amino containingoptionally substituted heteroaryl or unsaturated heterocyclic compoundhaving an aldehyde group alpha to both the amino group and anunsaturated ethylene amine moiety (628), for example, the commerciallyavailable 2-imidazolecarboxaldehyde. The coupling reaction is typicallyconducted using stoichiometric amounts of reagents (612) and (628), or amodest stoichiometric excess of reagent (612), and a weak base, e.g.,sodium carbonate, in an aqueous inert organic solvent, e.g., mixtures ofmethanol and water or mixtures of ethanol and water. The couplingreaction is typically conducted at temperatures in the range of 80° C.to 130° C. for 4 to 10 hours. The resulting product can be recovered byconventional methods, such as chromatography, filtration,crystallization, and the like, or can be used in the next step withoutpurification or isolation.

The intermediate from the coupling reaction (629) is reacted with aphosphonium ylide in a conventional Wittig reaction to form an alkeneintermediate (630). The Wittig reaction is typically conducted in aninert organic solvent such as tetrahydrofuran and the like and mayconveniently be conducted at approximately room temperature. Theresulting product can be recovered by conventional methods, such aschromatography, filtration, crystallization, and the like, or can beused in the next step without purification or isolation.

The alkene intermediate is reduced and cyclized to a quinoxalone ester(631) by contact, for example, with iron and acetic acid in an inertorganic solvent, e.g., ethanol, methanol, and the like. The reaction istypically conducted at temperatures in the range of 20 to 90° C. Theresulting product can be recovered by conventional methods, such aschromatography, filtration, crystallization, and the like, or can beused in the next step without purification or isolation.

In the next step, the ester group of the quinoxalone ester (631) ishydrolyzed under conventional conditions to yield the correspondingcarboxyl group (—COOH) or a suitable salt thereof. This reaction isconventionally effected by contacting the quinoxalone ester (631) with asuitable base, for example, lithium hydroxide monohydrate or sodiumhydroxide, in a solvent such as an aqueous inert organic solvent, e.g.,mixtures of tetrahydrofuran and water. The quinoxalone acetic acidintermediate is sulfonated in the manner described above with thedesired sulfonyl choloride RSO₂Cl to yield the sulfonated quinoxaloneacid intermediate (632).

The sulfonated quinoxalone acetic acid intermediate (632) is thencontacted with a primary or secondary amine NHR¹R² (606) (not shown)also in the manner described above to provide for compound 633, acompound of Formula I.

The compounds of Formula I, wherein Y is ═S, —OR⁸, —NR⁸, or —SR⁸, can beprepared as illustrated below in Scheme 11.

wherein R, R¹, R², R³, and R⁸ are as defined herein above with theexception that for NR⁸R⁸ one of R⁸ can be hydrogen.

The carbonyl group of the sulfonated quinoxalone ester (634) isconverted to the thiocarbonyl by conventional techniques such as contactwith a sulfurization agent such as Lawessen reagent. The sulfurizationreaction is conducted in an inert organic solvent, such astetrahydrofuran, at temperatures in the range of 20° C. to 100° C. for 1to 6 hours. The resulting product can be recovered by conventionalmethods, such as chromatography, filtration, crystallization, and thelike, or can be used in the next step without purification or isolation.

The thiocarbonyl compound (635) can then be alkylated to provide thedesired thioalkoxy derivative, compound 636. The alkylation reaction iseffected by conventional techniques such as by contacting thethiocarbonyl compound (635) with a lower alkyl iodide R⁸ (not shown),such as methyl iodide. The alkylation reaction is typically conducted inan inert organic solvent such as acetone, at temperatures at or nearroom temperature. The reaction is run to completion which typicallyoccurs within 1 to 6 hours. The resulting product can be recovered byconventional methods, such as chromatography, filtration,crystallization, and the like, or can be used in the next step withoutpurification or isolation.

Compound 636 can then be converted to the corresponding alkoxy compound—OR⁸ (637), wherein R⁸ is the same or different, by refluxing thethioquinoxalone (636) in an appropriate alcohol (R⁸OH). This reaction istypically conducted from 1 to 12 hours. The resulting product can berecovered by conventional methods, such as chromatography, filtration,crystallization, and the like, or can be used in the next step withoutpurification or isolation.

The ester side chain at the 2-position of the quinoxalone (637) is thenamidated by contact with a primary or secondary amine NHR¹R² (606) inthe manner described above. As is apparent, this procedure may requireconversion of the ester to the corresponding carboxyl group prior toamidation.

The thioquinoxalone (636) can also be converted to an amine —NR⁸R⁸,wherein each R⁸ is the same or different, by refluxing thethioquinoxalone (636) in the presence of appropriate amine (NHR⁸R⁸) inan inert organic solvent such as ethanol, methanol, and the like toprovide for compound 639. This reaction is typically conducted 6 to 15hours. The resulting product can be recovered by conventional methods,such as chromatography, filtration, crystallization, and the like, orcan be used in the next step without purification or isolation.

The ester side chain at the 2-position of the quinoxalone (639) is thenamidated by contact with a primary or secondary amine NHR¹R² (606) inthe manner described above. As is apparent, this procedure may requirehydrolysis of the ester to the corresponding carboxyl group prior toamidation.

As is apparent, the ester group in intermediates 635 and 636 can bedirectly hydrolyzed and then amidated in the manner described above toprovide for compounds of Formula I where Y is ═S or —SR⁸.

The starting materials for the above reactions are generally knowncompounds or can be prepared by known procedures or obviousmodifications thereof. For example, many of the starting materials areavailable from commercial suppliers such as Aldrich Chemical Co.(Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA), Emka-Chemce orSigma (St. Louis, Mo., USA). Others may be prepared by procedures, orobvious modifications thereof, described in standard reference textssuch as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15(John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds,Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989),Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March'sAdvanced Organic Chemistry, (John Wiley and Sons, 4^(th) Edition), andLarock's Comprehensive Organic Transformations (VCH Publishers Inc.,1989).

Sulfonyl chlorides of the formula RSO₂Cl as employed in the abovereaction are either known compounds or compounds that can be preparedfrom known compounds by conventional synthetic procedures. Suchcompounds are typically prepared from the corresponding sulfonic acid,i.e., from compounds of the formula R—SO₃H where R is as defined above,using phosphorous trichloride and phosphorous pentachloride. Thisreaction is generally conducted by contacting the sulfonic acid withabout 2 to 5 molar equivalents of phosphorous trichloride andphosphorous pentachloride, either neat or in an inert solvent, such asdichloromethane, at temperature in the range of about 0° C. to about 80°C. for about 1 to about 48 hours to afford the sulfonyl chloride.Alternatively, the sulfonyl chlorides can be prepared from thecorresponding thiol compound, i.e., from compounds of the formula R—SHwhere R is as defined herein, by treating the thiol with chlorine (Cl₂)and water under conventional reaction conditions.

Examples of sulfonyl chlorides suitable for use in this inventioninclude, but are not limited to, benzenesulfonyl chloride,1-naphthalenesulfonyl chloride, 2-naphthalenesulfonyl chloride,p-toluenesulfonyl chloride, α-toluenesulfonyl chloride,4-acetamidobenzenesulfonyl chloride, 4-amidinobenzenesulfonyl chloride,4-tert-butylbenzenesulfonyl chloride, 4-bromobenzenesulfonyl chloride,2-carboxybenzenesulfonyl chloride, 4-cyanobenzenesulfonyl chloride,3,4-dichlorobenzenesulfonyl chloride, 3,5-dichlorobenzenesulfonylchloride, 3,4-dimethoxybenzenesulfonyl chloride,3,5-ditrifluoromethylbenzenesulfonyl chloride, 4-fluorobenzenesulfonylchloride, 4-methoxybenzenesulfonyl chloride,2-methoxycarbonylbenzenesulfonyl chloride, 4-methylamidobenzenesulfonylchloride, 4-nitrobenzenesulfonyl chloride, 4-thioamidobenzenesulfonylchloride, 4-trifluoromethylbenzenesulfonyl chloride,4-trifluoromethoxybenzenesulfonyl chloride,2,4,6-trimethylbenzenesulfonyl chloride, 2-phenylethanesulfonylchloride, 2-thiophenesulfonyl chloride, 5-chloro-2-thiophenesulfonylchloride, 2,5-dichloro-4-thiophenesulfonyl chloride, 2-thiazolesulfonylchloride, 2-methyl-4-thiazolesulfonyl chloride,1-methyl-4-imidazolesulfonyl chloride, 1-methyl-4-pyrazolesulfonylchloride, 5-chloro-1,3-dimethyl-4-pyrazolesulfonyl chloride,3-pyridinesulfonyl chloride, 2-pyrimidinesulfonyl chloride and the like.If desired, a sulfonyl fluoride, sulfonyl bromide or sulfonic acidanhydride may be used in place of the sulfonyl chloride in the abovereactions.

Optionally substituted α,β-diaminobenzene compounds of the formula:

are either commercially available or can be prepared by conventionalmethods such as reduction of the corresponding α,β-dinitrobenzene,α-nitro-β-aminobenzene compounds and the like. When R⁷ is other thanhydrogen, derivatization of the amino group of the commerciallyavailable α-nitro-β-aminobenzene compound (2-nitroalinine (Aldrich)followed by reduction of the nitro group yields a compound of theformula:

Attachment of appropriate R³ groups can occur at any appropriate timeduring synthesis using conventional reactions.

Similarly, amines of the formula HNR¹R² (606) are either commerciallyavailable or can be prepared by methods well known in the art.

In some cases it may be more convenient to prepare a given productcompound or intermediate by preparing it from another product of FormulaI or intermediate, by applying known synthesis procedures. For example,as noted above, thiocarbonyl compounds (Y═S) are preferably preparedfrom the corresponding carbonyl compounds (Y═O) which are themselvescompounds of Formula I. Similarly, compounds where Y is —OR⁸, —SR⁸ or—NHR⁸ are prepared from the corresponding thiocarbonyl compounds (Y═S).

In a similar manner, when a compound of Formula I or an intermediatethereof has a substituents containing a hydroxyl group, the hydroxylgroup can be further modified or derivatized either before or after theabove coupling reactions to provide, by way of example, ethers,aldehydes, carboxylic acids, carbamates and the like.

Alternatively, a hydroxyl group present on a substituents of a compoundof Formula I or an intermediate thereof can be O-alkylating using theMitsunobu reaction. In this reaction, an alcohol, such as3-(N,N-dimethylamino)-1-propanol and the like, is reacted with about 1.0to about 1.3 equivalents of triphenyl-phosphine and about 1.0 to about1.3 equivalents of diethyl azodicarboxylate in an inert diluent, such astetrahydrofuran, at a temperature ranging −10° C. to about 5° C. forabout 0.25 to about 1 hour. About 1.0 to about 1.3 equivalents of ahydroxy compound, such as N-tert-butyltyrosine methyl ester, is thenadded and the reaction mixture is stirred at a temperature of about 0°C. to about 30° C. for about 2 to about 48 hours to provide theO-alkylated product.

In a similar manner, a compound of Formula I or an intermediate thereofcontaining a aryl hydroxy group can be reacted with an aryl iodide toprovide a diaryl ether. Generally, this reaction is conducted by formingthe alkali metal salt of the hydroxyl group using a suitable base, suchas sodium hydride, in an inert diluent such as xylenes at a temperatureof about −25° C. to about 10° C. The salt is then treated with about 1.1to about 1.5 equivalents of cuprous bromide dimethyl sulfide complex ata temperature ranging 10° C. to about 30° C. for about 0.5 to about 2.0hours, followed by about 1.1 to about 1.5 equivalents of an aryl iodide,such as sodium 2-iodobenzoate and the like. The reaction is then heatedto about 70° C. to about 150° C. for about 2 to about 24 hours toprovide the diaryl ether.

Additionally, a hydroxy-containing compound can also be readilyderivatized to form a carbamate. In one method for preparing suchcarbamates, a hydroxy compound of Formula I or an intermediate thereofis contacted with about 1.0 to about 1.2 equivalents of 4-nitrophenylchloroformate in an inert diluent, such as dichloromethane, at atemperature ranging −25° C. to about 0° C. for about 0.5 to about 2.0hours. Treatment of the resulting carbonate with an excess, preferablyabout 2 to about 5 equivalents, of a trialkylamine, such astriethylamine, for about 0.5 to 2 hours, followed by about 1.0 to about1.5 equivalents of a primary or secondary amine provides the carbamate.Examples of amines suitable for using in this reaction include, but arenot limited to, piperazine, 1-methylpiperazine, 1-acetylpiperazine,morpholine, thiomorpholine, pyrrolidin, piperidine and the like.

Alternatively, in another method for preparing carbamates, ahydroxy-containing compound is contacted with about 1.0 to about 1.5equivalents of a carbamyl chloride in an inert diluent, such asdichloromethane, at a temperature ranging 25° C. to about 70° C. forabout 2 to about 72 hours. Typically, this reaction is conducted in thepresence of a suitable base to scavenge the acid generated during thereaction. Suitable bases include, by way of example, tertiary amines,such as triethylamine, disopropylethylamine, N-methylmorpholine and thelike. Additionally, at least one equivalent (based on the hydroxycompound) of 4-(N,N-dimethylamino)pyridine is preferably added to thereaction mixture to facilitate the reaction. Examples of carbamylchlorides suitable for use in this reaction include, by way of example,dimethylcarbamyl chloride, diethylcarbamyl chloride and the like.

Likewise, when a compound of Formula I or an intermediate thereofcontains a primary or secondary hydroxyl group, such hydroxyl groups canbe readily converted into a leaving group and displaced to form, forexample, amines, sulfides and fluorides.

These reactions are typically conducted by first converting the hydroxylgroup into a leaving group, such as a tosylate, by treatment of thehydroxy compound with at least one equivalent of a sulfonyl halide, suchas p-toluenesulfonyl chloride and the like, in pyridine. This reactionis generally conducted at a temperature of 0° C. to about 70° C. forabout 1 to about 48 hours. The resulting tosylate can then be readilydisplaced with sodium azide, for example, by contacting the tosylatewith at least one equivalent of sodium azide in an inert diluent, suchas a mixture of N,N-dimethylformamide and water, at a temperatureranging 0° C. to about 37° C. for about 1 to about 12 hours to providethe corresponding azido compound. The azido group can then be reducedby, for example, hydrogenation using a palladium on carbon catalyst toprovide the amino (—NH₂) compound.

A further elaboration of appropriate reactions to form variousintermediates useful in this invention is found in, for example, allowedU.S. patent application Ser. No. 09/126,958 which is incorporated hereinby reference in its entirety.

Pharmaceutical Formulations

When employed as pharmaceuticals, the compounds of Formula I and II areusually administered in the form of pharmaceutical compositions. Thesecompounds can be administered by a variety of routes including oral,rectal, transdermal, subcutaneous, intravenous, intramuscular, andintranasal. These compounds are effective as both injectable and oralcompositions. Such compositions are prepared in a manner well known inthe pharmaceutical art and comprise at least one active compound.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, one or more of the compounds of Formula I andII above associated with pharmaceutically acceptable carriers. In makingthe compositions of this invention, the active ingredient is usuallymixed with an excipient, diluted by an excipient or enclosed within sucha carrier which can be in the form of a capsule, sachet, paper or othercontainer. When the excipient serves as a diluent, it can be a solid,semi-solid, or liquid material, which acts as a vehicle, carrier ormedium for the active ingredient. Thus, the compositions can be in theform of tablets, pills, powders, lozenges, sachets, cachets, elixirs,suspensions, emulsions, solutions, syrups, aerosols (as a solid or in aliquid medium), ointments containing, for example, up to 10% by weightof the active compound, soft and hard gelatin capsules, suppositories,sterile injectable solutions, and sterile packaged powders.

In preparing a formulation, it may be necessary to mill the activecompound to provide the appropriate particle size prior to combiningwith the other ingredients. If the active compound is substantiallyinsoluble, it ordinarily is milled to a particle size of less than 200mesh. If the active compound is substantially water soluble, theparticle size is normally adjusted by milling to provide a substantiallyuniform distribution in the formulation, e.g. about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions are preferably formulated in a unit dosage form, eachdosage containing 5 to about 100 mg, more usually about 10 to about 30mg, of the active ingredient. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient.

The active compound is effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It, willbe understood, however, that the amount of the compound actuallyadministered will be determined by a physician, in the light of therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, 0.1 to about 500 mg of the activeingredient of the present invention.

The tablets or pills of the present invention may be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably pharmaceutically acceptable solvents may be nebulized by useof inert gases. Nebulized solutions may be breathed directly from thenebulizing device or the nebulizing device may be attached to a facemasks tent, or intermittent positive pressure breathing machine.Solution, suspension, or powder compositions may be administered,preferably orally or nasally, from devices which deliver the formulationin an appropriate manner.

The following formulation examples illustrate the pharmaceuticalcompositions of the present invention.

FORMULATION EXAMPLE 1

Hard gelatin capsules containing the following ingredients are prepared:Quantity Ingredient (mg/capsule) Active Ingredient 30.0 Starch 305.0Magnesium stearate 5.0

The above ingredients are mixed and filled into hard gelatin capsules in340 mg quantities.

FORMULATION EXAMPLE 2

A tablet formula is prepared using the ingredients below: QuantityIngredient (mg/tablet) Active Ingredient 25.0 Cellulose,microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0

The components are blended and compressed to form tablets, each weighing240 mg.

FORMULATION EXAMPLE 3

A dry powder inhaler formulation is prepared containing the followingcomponents: Ingredient Weight % Active Ingredient 5 Lactose 95

The active mixture is mixed with the lactose and the mixture is added toa dry powder inhaling appliance.

FORMULATION EXAMPLE 4

Tablets, each containing 30 mg of active ingredient, are prepared asfollows: Quantity Ingredient (mg/tablet) Active Ingredient 30.0 mgStarch 45.0 mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone4.0 mg (as 10% solution in water) Sodium carboxymethyl starch 4.5 mgMagnesium stearate 0.5 mg Talc 1.0 mg Total 120 mg

The active ingredient, starch and cellulose are passed through a No. 20mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinyl-pyrrolidone is mixed with the resultant powders, which arethen passed through a 16 mesh U.S. sieve. The granules so produced aredried at 50° to 60° C. and passed through a 16 mesh U.S. sieve. Thesodium carboxymethyl starch, magnesium stearate, and talc, previouslypassed through a No. 30 mesh U.S. sieve, are then added to the granuleswhich, after mixing, are compressed on a tablet machine to yield tabletseach weighing 150 mg.

FORMULATION EXAMPLE 5

Capsules, each containing 40 mg of medicament are made as follows:Quantity Ingredient (mg/capsule) Active Ingredient 40.0 mg Starch 109.0mg Magnesium stearate 1.0 mg Total 150.0 mg

The active ingredient, cellulose, starch, an magnesium stearate areblended, passed through a No. 20 mesh U.S. sieve, and filled into hardgelatin capsules in 150 mg quantities.

FORMULATION EXAMPLE 6

Suppositories, each containing 25 mg of active ingredient are made asfollows: Ingredient Amount Active Ingredient   25 mg Saturated fattyacid glycerides to 2,000 mg

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2.0 g capacity and allowed to cool.

FORMULATION EXAMPLE 7

Suspensions, each containing 50 mg of medicament per 5.0 ml dose aremade as follows: Ingredient Amount Active Ingredient 50.0 mg Xanthan gum4.0 mg Sodium carboxymethyl cellulose (11%) Microcrystalline cellulose(89%) 50.0 mg Sucrose 1.75 g Sodium benzoate 10.0 mg Flavor and Colorq.v. Purified water to 5.0 ml

The medicament, sucrose and xanthan gum are blended, passed through aNo. 10 mesh U.S. sieve, and then mixed with a previously made solutionof the microcrystalline cellulose and sodium carboxymethyl cellulose inwater. The sodium benzoate, flavor, and color are diluted with some ofthe water and added with stirring. Sufficient water is then added toproduce the required volume.

FORMULATION EXAMPLE 8

Quantity Ingredient (mg/capsule) Active Ingredient 15.0 mg Starch 407.0mg Magnesium stearate 3.0 mg Total 425.0 mg

The active ingredient, cellulose, starch, and magnesium stearate areblended, passed through a No. 20 mesh U.S. sieve, and filled into hardgelatin capsules in 560 mg quantities.

FORMULATION EXAMPLE 9

An intravenous formulation may be prepared as follows: IngredientQuantity Active Ingredient 250.0 mg Isotonic saline  1000 mL

FORMULATION EXAMPLE 10

A topical formulation may be prepared as follows: Ingredient QuantityActive Ingredient 1-10 g Emulsifying Wax 30 g Liquid Paraffin 20 g WhiteSoft Paraffin to 100 g

The white soft paraffin is heated until molten. The liquid paraffin andemulsifying wax are incorporated and stirred until dissolved. The activeingredient is added and stirring is continued until dispersed. Themixture is then cooled until solid.

Another preferred formulation employed in the methods of the presentinvention employs transdermal delivery devices (“patches”). Suchtransdermal patches may be used to provide continuous or discontinuousinfusion of the compounds of the present invention in controlledamounts. The construction and use of transdermal patches for thedelivery of pharmaceutical agents is well known in the art. See, e.g.,U.S. Pat. No. 5,023,252, issued Jun. 11, 1991, which is incorporatedherein by reference in its entirety. Such patches may be constructed forcontinuous, pulsatile, or on demand delivery of pharmaceutical agents.

When it is desirable or necessary to introduce the pharmaceuticalcomposition to the brain, either direct or indirect techniques may beemployed. Direct techniques usually involve placement of a drug deliverycatheter into the host's ventricular system to bypass the blood-brainbarrier. One such implantable delivery system used for the transport ofbiological factors to specific anatomical regions of the body isdescribed in U.S. Pat. No. 5,011,472 which is incorporated herein byreference in its entirety.

Indirect techniques, which are generally preferred, usually involveformulating the compositions to provide for drug latentiation by theconversion of hydrophilic drugs into lipid-soluble drugs. Latentiationis generally achieved through blocking of the hydroxy, carbonyl,sulfate, and primary amine groups present on the drug to render the drugmore lipid soluble and amenable to transportation across the blood-brainbarrier. Alternatively, the delivery of hydrophilic drugs may beenhanced by intra-arterial infusion of hypertonic solutions which cantransiently open the blood-brain barrier.

Utility

The compounds of this invention are bradykinin antagonists and thereforeare suitable for use in blocking or ameliorating pain as well ashyperalgesia in mammals. Pain blocked or ameliorated by the compounds ofthis invention include, for example, pain associated with surgicalprocedures, burns, trauma, migraine, and the like.

The compounds of this invention are also useful in the treatment ofdisease conditions in a mammal which are mediated at least in part bybradykinin. Examples of such disease conditions include asthma,rhinitis, premature labor, inflammatory arthritis, inflammatory boweldisease, endotoxic shock related to bacterial infections, centralnervous system injury, back pain, neuropathic pain, spinal cord injuryand the like.

As noted above, the compounds of this invention are typicallyadministered to the mammal in the form of a pharmaceutical composition.Pharmaceutical compositions of the invention are suitable for use in avariety of drug delivery systems. Suitable formulations for use in thepresent invention are found in Remington's Pharmaceutical Sciences, MacePublishing Company, Philadelphia, Pa., 17th ed. (1985).

In order to enhance serum half-life, the compounds may be encapsulated,introduced into the lumen of liposomes, prepared as a colloid, or otherconventional techniques may be employed which provide an extended serumhalf-life of the compounds. A variety of methods are available forpreparing liposomes, as described in, e.g., Szoka, et al., U.S. Pat.Nos. 4,235,871, 4,501,728 and 4,837,028 each of which is incorporatedherein by reference.

The amount administered to the patient will vary depending upon what isbeing administered, the purpose of the administration, such asprophylaxis or therapy, the state of the patient, the manner ofadministration, and the like all of which are within the skill of theattending clinician. In therapeutic applications, compositions areadministered to a patient already suffering from a disease in an amountsufficient to cure or at least partially arrest the symptoms of thedisease and its complications. An amount adequate to accomplish this isdefined as “therapeutically effective dose.” Amounts effective for thisuse will depend on the disease condition being treated as well as by thejudgment of the attending clinician depending upon factors such as theseverity of the inflammation, the age, weight and general condition ofthe patient, and the like.

The compositions administered to a patient are in the form ofpharmaceutical compositions described above. These compositions may besterilized by conventional sterilization techniques, or may be sterilefiltered. The resulting aqueous solutions may be packaged for use as is,or lyophilized, the lyophilized preparation being combined with asterile aqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of the compounds of the present invention willvary according to, for example, the particular use for which thetreatment is made, the manner of administration of the compound, thehealth and condition of the patient, and the judgment of the prescribingphysician. For example, for intravenous administration, the dose willtypically be in the range of about 20 μg to about 500 μg per kilogrambody weight, preferably about 100 μg to about 300 μg per kilogram bodyweight. Suitable dosage ranges for intranasal administration aregenerally about 0.1 pg to 1 mg per kilogram body weight. Effective dosescan be extrapolated from dose-response curves derived from in vitro oranimal model test systems.

In addition to the above, the esters and thioesters of Formula I areuseful intermediates in the preparation of the amides of Formula I(W═N).

The following synthetic and biological examples are offered toillustrate this invention and are not to be construed in any way aslimiting the scope of this invention. Unless otherwise stated, alltemperatures are in degrees Celsius.

EXAMPLES

In the examples below, the following abbreviations have the followingmeanings. If an abbreviation is not defined, it has its generallyaccepted meaning.

-   -   Boc=t-butoxycarbonyl    -   brd=broad doublet    -   brm=broad multiplet    -   brt=broad triplet    -   bs=broad singlet    -   conc.=concentrated    -   dba=dibenzyledene acetone    -   dd=doublet of doublets    -   DCC=dicyclohexylcarbodiimide    -   DIAD=diisopropyl azo dicarboxylate    -   DIEA diisopropylethyl amine    -   DMAP=4-N,N-dimethylaminopyridine    -   DME=dimethoxyethane    -   DMF=N,N-dimethylformamide    -   DPPA=diphenylphosphoryl azide    -   dppf=1,1′-bis(diphenylphosphino)ferrocene    -   dt=doublet of triplets    -   EDCI=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride    -   eq.=equivalents    -   g=gram    -   h=hours    -   HATU=O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetraethyluronium        hexafluorophosphate    -   HOAc acetic acid    -   HOBT=1-hydroxybenzothiazole hydrate    -   HPLC=high performance liquid chromatography    -   LC/MS=liquid chromatography/mass spectroscopy    -   m=multiplet    -   M=molar    -   mg=milligram    -   min.=minutes    -   mL=milliliter    -   mm=millimeter    -   mmol=millimol    -   N=normal    -   psi=pounds per square inch    -   PS-DCC=polysupported dicyclohexylcarbodiimide    -   PS-DIEA=polysupported diisopropylethyl amine    -   q=quartet    -   rpm=rotations per minute    -   rt=room temperature    -   R_(t)=retention time    -   s=singlet    -   t=triplet    -   TEA=triethylamine    -   TFA=trifluoroacetic acid    -   THF=tetrahydrofuran    -   TLC=thin layer chromatography    -   μL=microliters    -   % mol=mol percent

In the following examples and procedures, the term “Aldrich” indicatesthat the compound or reagent used in the procedure is commerciallyavailable from Aldrich Chemical Company, Inc., Milwaukee, Wis. 53233USA; the term “Lancaster” indicates that the compound or reagent iscommercially available from Lancaster Synthesis, Inc., N.H. 03087 USA;the term “Sigma” indicates that the compound or reagent is commerciallyavailable from Sigma, St. Louis Mo. 63178 USA; the term “Maybridge”indicates that the compound or reagent is commercially available fromMaybridge Chemical Co. Trevillett, Tintagel, Cornwall PL34 OHW UnitedKingdom; and the term “TCI” indicates that the compound or reagent iscommercially available from TCI America, Portland Oreg. 97203; the term“Frontier Scientific” indicates that the compound or reagent iscommercially available from Frontier Scientific, Utah, USA; the term“Specs” indicates that the compound or reagent is commercially availablefrom Netherlands; and “Bachem” indicates that the compound or reagent iscommercially available from Bachem, Torrance, Calif., USA.

Unless otherwise specified, the following equipment, settings andmaterials were used in the foregoing examples.

NMR spectra were recorded on a Varian or Bruker 300 spectrometer. ¹³Cand ¹H were referenced to TMS. Exact mass measurements were performed onan Agilent 1100-MSD mass spectrometer, equipped with a standardelectrospray ionization interface. Routine HPLC's were acquired on anAgilent 1100-MSD, using an acetonitrile:water-0.1% TFA solventsystem-1.5 ml/mn. The gradient of acetonitrile ranged from 20% to 70%over a period of 2.33 min.

The procedures set forth in Methods A-C below are illustrated in thefollowing reaction scheme:

Method A General Procedure for the Coupling Reaction Between1,2-Fluoronitrobenzene and an Aminoacid [Exemplified by Preparation of(R)-2-(2-Nitrophenylamino)-succinic acid dimethyl ester]

A mixture of 1,2-fluoronitrobenzene (27.5 g, 19.5 mmol), D-aspartic acid(20.7 g, 15.6 mmol) and sodium carbonate (49.5 g, 46.7 mmol) in a mixedsolvent system of ethanol-water (5:1, 300 mL) was heated at 105° C.overnight. The solvent was removed under reduced pressure and DMF (200mL) was then added to the residue. Methyl iodide (24 mL, 38.5 mmol) wasadded to the mixture and the resulting mixture was stirred at rtovernight. Solvent was removed under reduced pressure and EtOAc wasadded to the residue. The heterogeneous mixture was then washed withbrine, dried with MgSO₄, and concentrated under reduced pressure. Theresulting yellow oil was purified by column chromatography over silicagel with EtOAc/hexane (1:2) as eluent to give a yellow oil as the titlecompound: ¹H NMR (CDCl₃) δ=10.24 (bs, 1H), 8.03 (t, 1H, J=5.4 Hz),7.30-7.15 (m, 5H), 6.75-6.70 (m, 3H), 6.61-6.56 (m, 1H), 5.79 (bs, 1H),4.08-4.04 (m, 1H), 3.30-3.24 (m, 2H), 2.71 (t, 2H, J=7.8 Hz), 2.60 (dd,1H, J=3.9, 15.3 Hz), 2.31 (dd, 1H, J=8.7, 15.3 Hz).

Method B General Procedure of the Preparation of the QuinoxalineSkeleton Using Reduction-Cyclization Sequence [Exemplified bypreparation of (R)-(3-Oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl)-aceticacid methyl ester]

A mixture of 2-(R)-(2-nitrophenylamino)succinic acid dimethyl ester(2.15 g, 7.62 mmol) (prepared below), and PtO₂ (210 mg) in methanol (35mL) was shaken on a Parr apparatus at 48 psi for 6 hours. The reactionwas filtered through celite, rinsed with methanol and was evaporated invacuo to a very sticky oil as the title compound (1.69 g, 100%): ¹H NMR(CDCl₃) δ=8.23 (bs, 1H), 6.91 (dt, 1H, J=1.8, 7.5 Hz), 6.80-6.70 (m,3H), 4.74 (bs, 1H), 4.34 (dt, 1H, J=2.4, 10.5 Hz), 3.75 (s, 3H), 3.14(dd, 1H, J=2.4, 17.4 Hz), 2.75 (dd, 1H, J=10.5, 17.4 Hz).

Method C General Procedure of Ethyl Chloroformate Coupling Reaction[Exemplified by Preparation of2-(3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl)-N-phenethyl-acetamide]

To the solution of (3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl)-acetic acid(510 mg, 2.48 mmol) in THF (18 mL) was added triethylamine (0.38 ml,2.74 mmol) and ethyl chloroformate (0.24 ml, 2.74 mmol). The mixture wasstirred at rt for 1.5 hours and then phenethylamine (0.34 ml, 2.74 mmol)was added. The resulting mixture was again stirred at rt for 4.5 hours.The precipitate was filtered off and washed with small amount of THF afew times. The solvent was removed under the reduced pressure to givethe title compound as a yellow solid: ¹H NMR (DMSO-d₆) δ=10.24 (bs, 1H),8.03 (t, 1H, J=5.4 Hz), 7.30-7.15 (m, SH), 6.75-6.70 (m, 3H), 6.61-6.56(m, 1H), 5.79 (bs, 1H), 4.08-4.04 (m, 1H), 3.30-3.24 (m, 2H), 2.71 (t,2H, J=7.8 Hz), 2.60 (dd, 1H, J=3.9, 15.3 Hz), 2.31 (dd, 1H, J=8.7, 15.3Hz).

Method D General Procedure of Ethyl Chloroformate Coupling Reaction[Exemplified by Preparation of2-(3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl)-N-phenethyl-acetamide]

To the solution of (3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl)-acetic acid(510 mg, 2.48 mmol) in THF (18 mL) was added triethylamine (0.38 ml,2.74 mmol) and ethyl chloroformate (0.24 ml, 2.74 mmol). The mixture wasstirred at rt for 1.5 hours and then phenethylamine (0.34 ml, 2.74 mmol)was added. The resulting mixture was again stirred at rt for 4.5 hours.The precipitate was filtered off and washed with small amount of THF afew times. The solvent was removed under the reduced pressure to givethe title compound as a yellow solid: ¹H NMR (DMSO-d₆) δ=10.24 (bs, 1H),8.03 (t, 1H, J=5.4 Hz), 7.30-7.15 (m, 5H), 6.75-6.70 (m, 3H), 6.61-6.56(m, 1H), 5.79 (bs, 1H), 4.08-4.04 (m, 1H), 3.30-3.24 (m, 2H), 2.71 (t,2H, J=7.8 Hz), 2.60 (dd, 1H, J=3.9, 15.3 Hz), 2.31 (dd, 1H, J=8.7, 15.3Hz).

Method E below illustrates an alternative method for ester hydrolysisusing sodium hydroxide.

Method E General Procedure for Ester Hydrolysis Using Sodium Hydroxide[Exemplified by Preparation of(3-Oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl)acetic acid]

2-(3-Oxo-1,2,3,4-tetrahydroquinoxalin-2-yl)-acetamide (22 g, 0.11 mol)was dissolved in 10% NaOH (600 mL) and was heated under reflux for 3hours. The mixture was cooled down via an ice-bath and was acidifiedwith pre-cooled 10% HCl to pH˜6. The solvent was concentrated and theresulting precipitate was isolated via filtration to give a gray solidas the title product: ¹H NMR (DMSO-d₆) δ=12.35 (bs, 1H), 10.25 (bs, 1H),6.74-6.68 (m, 3H), 6.61-6.58 (m, 1H), 5.91 (bs, 1H), 4.08-4.04 (m, 1H),2.69 (dd, 1H, J=5.1, 16.2 Hz), 2.51 (dd, 1H, J=6.9, 16.2 Hz)

The procedures set forth in Methods F-G below are illustrated in thefollowing reaction scheme:

Method F General Procedure of the Preparation of the QuinoxalineSkeleton Using Maleimide and Phenylenediamine [Exemplified byPreparation of 2-(3-Oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl)acetamide]

To a solution of 1,2-phenylenediamine (21.5 g, 0.2 mol) in water (450mL) was added dropwise a solution of maleimide, (20.0 g, 0.2 mol) inmethanol (180 mL) over 60 min. The mixture was then stirred at 95° C.for 2 hours followed at rt overnight. The precipitate was collected viafiltration and was washed with small amount of water for a few times toyield the title compound as a pale gray solid (pure product): ¹H NMR(DMSO-d₆) δ=10.2 (bs, 1H), 7.37 (bs, 1H) 6.88 (bs, 1H), 6.74-6.68 (m,3H), 6.31-6.57 (m, 1H), 5.78 (bs, 1H), 4.08-4.04 (m, 1H), 2.63 (dd, 1H,J=3.6, 15.5 Hz), 2.32 (dd, 1H, J=3.3, 15.5 Hz); HPLC (CH₃CN—H₂O-0.1%TFA): R_(t)=9.49 min.

Method G General Procedure for the Preparation of SulfonatedQuinoxalinyl Carboxyamide [Exemplified by Preparation of[3-oxo-1-arylsulfonyl-1,2,3,4-tetrahydroquinoxalin-2-yl]-acetamide]

Arylsulfunyl chloride (1 mmole) was added to a stirred solution of3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl-acetamide (1 mmole) in pyridineat 0° C. The reaction was allowed to warm up to rt. Additional stirringwas continued at rt for 18-24 h. Excess solvent was removed underreduced pressure and the residue was washed with saturated NaHCO₃solution. The solid residue was filtered off and dried. The titleproduct is obtained either by recrystallization (MeOH) or by using acolumn chromatography (CH₂Cl₂—MeOH, 95:5)

Method H below illustrates an alternative method for the preparation ofsulfonated quinoxalinyl carboxyacids.

Method H General Procedure for the Preparation of SulfonatedQuinoxalinyl Carboxylic Acid [Exemplified by Preparation of[3-Oxo-[-(2,4,6-trimethyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoxalin-2-yl]-aceticacid]

The solution of starting material lithium salt (81.7 mmol, 17.3 g) inwater (500 mL) was stirred in a 3-necked round bottom flask at roomtemperature under an argon atmosphere. To the solution was added2,5-dimethyl-4-chlorobenzene sulfonyl chloride (32.2 g, 135 mmol) inportions over 20 min. The reaction mixture was left to stir for 18 hoursat room temperature under an argon atmosphere. The pH dropped from 9.0to weakly acidic (approximately pH 5). A light yellowish solid wasfiltered off, and rinsed with water. The solid was transferred to aflask containing water (200 mL) and 10% NaOH (15-20 mL) was added to apH of approximately 9.0. Not all of the solid dissolved. The insolublematerial was filtered off and the filtrate was extracted with EtOAc (100mL) to remove traces of sulfonyl chloride. The aqueous phase was cooledin an ice bath then acidified with 2M HCl to approximately 4.0. Aprecipitate was filtered off and rinsed with cold water then air dried.

¹H NMR (DMSO-d₆) δ=12.51 (s, 1H), 10.71 (bs, 1H), 7.28 (dt, 1H, J=1.6,8.4 Hz), 7.07-7.10 (m, 3H), 7.01 (dt, 1H, J=1.6, 8.4 Hz), 6.95 (dd, 1H,J=1.6, 8.4 Hz), 4.66 (dd, 1H, J=4.4, 10.4 Hz), 2.45-2.49 (m, 1H), 2.36(s, 6H), 2.28 (s, 3H), 2.13 (dd, 1H, J=10.4, 15.2 Hz).

The procedures set forth in Method I below are illustrated in thefollowing reaction scheme:

Method I General Procedure for Preparing Sulfonated QuinoxalinylCarboxyamide [Exemplified by Preparation of[3-Oxo-1-arylsulfonyl-1,2,3,4-tetrahydroquinoxalin-2-yl]-acetamide]

The 3-oxo-1-arylsulfonyl-1,2,3,4-tetrahydroquinoxalin-2-yl carboxylicacid (12.19 mmol), a primary or secondary amine (14.73 mmol) and TEA(34.34 mmol) were dissolved in dry DMF (50 mL) and cooled to 0° C. Tothe above stirred solution, DPPA (14.62 mmol neat) was added slowly over20 min. and the reaction was allowed to warm to rt. After stirring for18 h at rt, excess DMF was removed under reduced pressure. Water (50mL), saturated NaHCO₃ (50 mL) and ethyl acetate (100 mL) were added to acrude residue and the reaction mixture was sonicated for 10 min. Thetitle product was filtered off and dried.

The procedures set forth in Method J below are illustrated in thefollowing reaction scheme:

Method J General Procedure for the Preparation of1,2,3,6-tetrahydro-N-alkylpyridine Derivatives

A suitable starting material comprising a 2-acetamide group on the1,2,3,4-tetrahydroquinoxaline having a pyridine functionality attachedthereto (2.92 mmol) was added to dry DMF (15 ml) and heated with aheat-gun (if required) to form a clear solution and cooled to rt. Methyliodide (5 mL, excess) was added to it and stirring continued for 18 h atrt. Excess DMF was removed under reduced pressure and the pyridiniumsalt formed was taken to the next step without further purification. Themethyl iodide salt was dissolved in methanol (25 mL) and NaBH₄ (13.78mmol) was added to it and stirred for 1 h. Excess MeOH was removed andwater (50 ml) was added to the crude product and sonicated for 10 min. Asolid product containing the 1,2,3,6-tetrahydro-N-methylpyridine groupwas filtered off or extracted with CH₂Cl₂ and used in the next stepwithout further purification.

The remaining double bond in the 1,2,3,6-tetrahydro-N-methylpyridinegroup can optionally be hydrogenated to provide for theN-methylpiperidin-4-yl derivative.

A process for reduction of the heterocyclic double bond is provided inMethod K and is illustrated in the reaction scheme below:

Method K General Procedure of the Preparation of N-alkylpiperidineDerivatives from 1,2,3,6-tetrahydro-n-alkylpyridine Compounds

N-methyl-1,2,3,6-tetrahydropyridine (0.1 moles) was dissolved inmethanol (25 mL) and transferred to a Parr hydrogenation bottle. 10%Dilute HCl (10 mL) and PtO₂(3.00 mg) were added to it and the mixturewas hydrogenated at 45 psi for 18 h. The catalyst was filtered off overcelite. Excess solvent was removed and the crude material was driedovernight on high vacuum pump to afford the title compound.

The processes set forth in Method L are illustrated in the followingreaction schemes:

Method L General Procedure for the Preparation ofN-Cyclopropylpiperidinylethyl Acetamides [Exemplified by Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]N-[2-(N-cyclopropylpiperidin-4-yl)eth-1-yl]acetamide]

Step A:2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamide,prepared by amidation of the corresponding carboxylic acid with2-(2-aminoethyl)pyridine (TCI) in the manner described above washydrogenated in the presence of platinum oxide (PtO₂) in methanol toprovide for2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetra-hydroquinoxalin-2-yl]-N-[2-(piperidin-4-yl)eth-1-yl]acetamide.

Step B: Sodium cyanoborohydride (1.5 mmol) was added to a stirredsolution of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]-N-[2-(N-cyclopropylpiperidin-4-yl)eth-1-yl]acetamide(1 mmol), with 1-ethoxy-1-trimethylsiloxy cyclopropane (1 mmol) (AldrichChemical Company) and AcOH (1 mmol) in MeOH (20 mL) at rt. After beingstirred at rt, the reaction mixture was refluxed for 18 h. The excesssolvent was removed and washed with saturated NaHCO₃ solution. Theaqueous solution was extracted with CH₂Cl₂ (2×100 mL). The combinedorganic layers were dried and concentrated. The resulting residue wasthen purified by silica gel column chromatography (CH₂Cl₂—MeOH 95:5) toafford the title compound as a solid.

The process set forth in Method M is illustrated in the followingreaction scheme:

Method M General Procedure for the Preparation ofN-Phenylpiperidinylethyl Acetamides [Exemplified by Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]N-[2-(N-phenylpiperidin-4-yl)eth-1-yl]acetamide]

Triphenylbismuth diacetate (Ph₃Bi(OAc)₂ (1.2 eq.) and Cu(OAc)₂ (0.12eq.) were added to a stirred solution of2-[2-(R,S)-1-(4-chloro-2,5-dimethyl-enzenesulfonyl)-3-oxo-1,2,3,4-tetra-hydroquinoxalin-2-yl]-N-[2-(piperidin-4-yl)eth-1-yl]acetamide(1 mmol) in dichloromethane at rt and stirred for 18 h. The reactionmixture was partitioned between dichloromethane (50 mL) and water (50mL) and stirred for 2 h. The organic layer was separated, dried andconcentrated. The residue was chromatographed on silica gel using(CH₂Cl₂—MeOH 90:10) affording the title compound.

The process set forth in Method N is illustrated in the followingreaction scheme:

Method N General Procedure for the Preparation ofN-Pyridylpiperidinylethyl Acetamides [Exemplified by Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]N-[2-((N-pyrid-4-yl)piperidin-4-yl)eth-1-yl]acetamide]

A solution of2-[2-(R,S)-1-(4-chloro-2,5-dimethyl-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(piperidin-4-yl)eth-1-yl]acetamide(0.1 mmol) and 4-chloropyridine (excess) in EtOH (5 mL) was heated in asealed tube at 110° C. for 16 h. Excess solvent was removed and theresidue purified by preparative HPLC (acetonitrile-water-0.1% TFA) andthe title compound was isolated as the TFA salt.

Method O General Procedure for Removal of Boc Protecting Groups fromAmino Groups

To a stirred solution of Boc-amine (0.01 mole) in dry ethyl acetate (25mL) at 0° C., HCl gas was bubbled for 15 min. The reaction solution wasstirred for 5 h at rt after which the HCl salt was recovered byfiltration. The HCl salt was used in the next step without furtherpurification.

Method P General Procedure for Removal of Boc Protecting Groups fromAmino Groups

HCl gas was bubbled for 2 h into a solution of Boc amino acid in dryMeOH (100 mL) at rt. The reaction solution was stirred for 18 h at rtafter which the product was recovered upon solvent removal. The HCl saltwas used in the next step without further purification.

The processes set forth in Methods Q and R are illustrated in thefollowing reaction scheme:

Method Q General Procedure for the Preparation of Vinylidene Groups atthe 2-Position of 3-Oxo-3,4-dihydro-1-H-quinoxalines [Exemplified byPreparation of 2-[3-oxo-3,4-dihydro-1H-quinoxalin-2-ylidine acetic acidethyl ester]

Phenylene diamine (0.1 mmol) (available, e.g., from Aldrich) in CH₂Cl₂was added to a stirred solution of 2-keto-glutonoic acid diethyl ester(0.1 mmol) (Aldrich) in MeOH at rt. After being stirred 1 h, at rt, asolid product was filtered out and purified by washing with CH₂Cl₂. Theproduct formed was used in the next step without further purification.

Method R General Procedure for Hydrogenation of Vinylidene Groups[Exemplified by Preparation of2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-Acetic Acid EthylEster]

Sodium cyanoborohydride (7.95 mmol) was added to a stirred solution of2-[3-oxo-3,4-dihydro-1H-quinoxalin-2-ylidene acetic acid ethyl ester(2.23 mmol), in THF-AcOH (25.5 mL, 2:1) under argon at rt. Afterstirring for 20 min, the solvent was evaporated under reduced pressure,the crude residue was resuspended in water (200 mL) and extracted withCH₂Cl₂ (3×50 mL) or filtered. The combined organic layers were washedwith water and dried over anhydrous Na₂SO₄. After evaporation of thesolvent, the crude oil was purified by silica gel column chromatography(eluents: CH₂Cl₂+MeOH (95:5), to give the title compound.

Method S General Procedure for Making the Sulfonated QuinoxalinylCarboxyamide from the Corresponding Carboxylic Acid

The starting carboxylic acid (200 mg; 0.48 mmol) was dissolved in dryDMF (50 mL) maintained at rt under N₂. To this was added Et₃N (3.0 eq),HOBT (1.1 eq) and the amine of choice (1.1 eq). The reaction was stirredat −10° C. for about 15 min. EDCI (1.1 eq) was then added and thereaction mixture warmed up to rt and stirred overnight. EtOAc (100 mL)was added. The organic layer was washed with saturated NaHCO₃ (3×50 mL);10% HCl (3×50 mL) and brine (6×50 mL). The organic layer was dried overMgSO₄. Upon filtration, the solvent was removed under reduced pressure.A column chromatography (silica gel) using EtOAc/hexanes 1:4 affordedthe amidated product.

The processes set forth in Method T are illustrated in the followingreaction scheme:

Method T General Procedure for Conversion of a Cyanophenyl Group to a4,5-Dihydroimidazol-2-ylphenyl Group [Exemplified by the Preparation of2-[2-(R,S)-[-arylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[-(N-pyrrolidinylcarbonyl)-2-(4-(4,5-dihydroimidazol-2-yl)phenyl)eth-1-yl]acetamide]

2-[2-(R,S)-1-Arylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(N-pyrrolidinylcarbonyl)-2-(4-cyanophenyl)eth-1-yl]acetamide](1g; 1.57 mmol) was dissolved in a solution of Et₃N/pyridine (6 mL/60 mL)at rt. H₂S was bubbled through for 15 min. at rt. The reaction mixturewas then capped and stirred at rt overnight. The solvent mixture wasremoved under reduced pressure and the resulting residue was thendissolved in a mixture of acetone/iodomethane (60 mL:5 mL). The solutionwas heated to reflux for 1.5 h whereupon the solvent was removed underreduced pressure. The crude material was dissolved in dry MeOH (15 mL),with Et₃N (1.0 eq; 220 μL) and ethylenediamine (1.1 eq; 120 μL). Thesolution was refluxed for 2 days. The solvent was evaporated underreduced pressure. The crude material was submitted for purification byreverse phase HPLC (acetonitrile/water-0.1% TFA), and the resultingproduct isolated.

The processes set forth in Method U are illustrated in the followingreaction scheme:

Method U General Procedure for Conversion of a Vinylpyridine Group to a2-Aminoethylpyridine Group [Exemplified by the Preparation of2-(N-isopropyl)-eth-1-yl-pyridine]

4-Vinyl pyridine (1.6 mL; 15 mmol) was dissolved in acetic acid (12.5mmol; 0.72 mL) and isopropylamine (12.5 mmol; 1.06 mL). The reactionmixture was refluxed for 6 h. The solvent was evaporated under reducedpressure. To the resulting solid was added EtOAc as well as saturatedNaHCO₃. The organic layer was isolated, dried over MgSO₄. The solventwas removed under reduced pressure. The desired material was isolated asa foam. H¹ NMR (CDCl₃) δ=8.4 (m, 2H); 7.05 (m, 2H); 2.75 (m, 2H); 2.65(m, 3H); 0.99 (d, 6H). C¹³ NMR (CDCl₃) 149.87; 149.54; 149.09; 123.93;48.19; 47.20; 35.56; 22.43. MS (ES) m/e (API-ES)=165 (M+H).

The processes set forth in Method V are illustrated in the followingreaction scheme:

Method V General Procedure for the Preparation ofN-methyl-N-(2-pyrid-4-yl-ethyl)Acetamides [Exemplified by thePreparation of2-[1-(4-Chloro-2,5-dimethyl-benzenesulfonyl)-4-methyl-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]-N-methyl-N-(2-pyridin-4-yl-ethyl)-acetamide]

Step A: Preparation of4-methyl-3-oxo-3,4-dihydro-1H-quinoxalin-2-ylidene-acetic acid ethylester

To a solution of N-methyl-1,2-phenylenediamine (6.1 g, 4.99 mmol) inMeOH (50 mL) was added in portion of oxalacetic acid diethyl ester (9.9g, 5.26 mmol). The mixture was then stirred at rt for 1 h. Theprecipitate was collected via filtration and was washed with smallamount of methanol to yield a pale brownish solid as the pure product:¹H NMR (DMSO-d₆) δ=11.1 (bs, 1H), 7.45-7.42 (m, 1H), 7.32-7.29 (m, 1H),7.15-7.10 (m, 2H), 5.53 (s, 1H), 4.14 (q, J=9.0 Hz, 2H), 3.51 (s, 3H),1.23 (t, J=9.0 Hz, 3H); HPLC (CH₃CN—H₂O-0.1% TFA) (short column):R_(t)=3.91 min.

Step B:Preparation of4-methyl-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl-acetic acid ethylester

4-Methyl-3-oxo-3,4-dihydro-1H-quinoxalin-2-ylidene-acetic acid ethylester (1.1 g, 4.47 mmol) was suspended in 25 mL of MeOH/HOAc (2:1) at rtand sodium cyanoborohydride was added portionwise (281 mg, 4.47 mmol).The mixture became clear after five minutes and was continuously stirredat rt for 2 hours. The solvent was removed under reduced pressure. Thecrude residue was mixed with water (50 mL) and extracted with EtOAc(3×40 mL). The organic layers were combined, washed with water, brineand dried over MgSO₄. After removal of the solvent, a pale brown oil wasobtained as the desired pure product: ¹H NMR (CDCl₃) δ=6.97-6.94 (m,3H), 6.74 (d, J=9.0 Hz, 1H), 4.28 (dd, J=3.0, 9.0 Hz, 1H), 4.23 (q,J=9.0 Hz, 2H), 3.37 (s, 3H), 3.11 (dd, J=3.0, 18.0 Hz, 1H), 2.68 (dd,J=9.0, 19.0 Hz, 1H), 1.28 (t, J=9.0 Hz, 3H).

Step C:Preparation of lithium[(4-methyl-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl)]-acetate

4-Methyl-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl-acetic acid ethylester (1.05 g, 4.23 mmol) was dissolved in a mixed solvent THF/H₂O (1:1,39 mL) and cooled to 0° C. in an ice-bath. Lithium hydroxide monohydrate(174 mg, 4.15 mmol) was then added and the resulting mixture was stirredat 0° C. for 6 h (monitored by TLC). Solvent was removed under reducedpressure and the residue was triturated with EtOAc to give the titlecompound as a gray solid: ¹H NMR (D₂O) δ=7.03-6.79 (m, 4H), 4.06 (dd,1H, J=4.5, 9.6 Hz), 3.21 (s, 3H), 2.48 (dd, 1H, J=9.3, 15.6 Hz), 2.33(dd, 1H, J=4.5, 15.6 Hz).

Step D: Preparation of1-[(4-Chloro-2,5-dimethyl-benzenesulfonyl)-4-methyl-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]-aceticacid

Lithium (4-methyl-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl)-acetate and4-chloro-2,5-dimethylbenzenesulfonyl chloride (Lancaster) were reactedusing Method H above to provide the title compound for this step.

¹H NMR (DMSO-d₆) δ=7.51-7.44 (m, 4H), 7.28 (dt, J=1.2, 7.8 Hz, 1H), 7.18(d, J=7.8 Hz, 1H), 4.97 (dd, J=3.9, 10.5 Hz, 1H), 2.76 (s, 3H),2.56-2.49 (m, 1H), 2.28 (s, 3H), 2.16 (dd, J=10.5, 15.3 Hz, 1H), 2.00(s, 3H).

Step E: Preparation of2-[1-(4-Chloro-2,5-dimethylbenzene-sulfonyl)-4-methyl-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]-N-(2-pyridin-4-yl-ethyl)]acetamide

1-(4-Chloro-2,5-dimethyl-benzenesulfonyl)-4-methyl-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]-aceticacid and 4-(2-aminoeth-1-yl)pyridine (TCI) were coupled using Method Ito give the desired material. ¹H NMR (D₂O) δ=8.52-8.50 (m, 2H), 8.04 (t,J=5.4 Hz, 1H), 7.49-7.39 (m, 4H), 7.27-7.22 (m, 3H), 7.16 (d, J=8.1 Hz,1H), 5.03 (dd, J=4.8, 8.7 Hz, 1H), 3.37-3.21 (m, 2H), 2.77-2.67 (m, 5H),2.27 (s, 3H), 2.27-2.11 (m, 2H), 2.00 (s, 3H);); HPLC (CH₃CN—H₂O-0.1%TFA) (short column): R_(t)=3.71 min.

The procedures set forth in Methods W through Z below are illustrated inthe following general reaction scheme. It is noted that this reactionscheme merely illustrates the amidation of the carboxyl goup with theappropriate amine and that the specific conditions used in each Methodvaries to account for the particulars of that Method. It is furthernoted that while a primary amine is illustrated below, secondary aminescan also be used:

Method W General Procedure for Amidating a Carboxylic Acid

Into a vial was placed 0.22 mg of an amine or amine hydrochloride salt.A solution was then prepared by dissolving 2.45 g of acid (5.99 mol),0.90 g of 1-hydroxy-7-azabenzotriazole, and 2.5 mL of triethylamine insufficient dimethylacetamide to give a total volume of 30 mL. The aminewas treated with 1.0 mL of this solution and briefly agitated, and thentreated with 1.0 mL of 0.26 M solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in dimethylacetamide. Themixtures was agitated for 24 h then diluted with 3 mL ofdimethylacetamide and treated with 2.5 mL of Biorad AG 50W-8X strongacid ion exchange resin and 2.5 mL of Amerlite MP-3 mixed bed ionexchange evaporated at reduced pressure. The product was then dissolvedin diethyl ether or in ethyl acetate and precipitated by the addition ofhexane and collected by filtration and dried in a stream of air.

Method X General Procedure for Amidating a Carboxylic Acid

5.5 mmol of HOBT in 10 mL of dry DMF was added via a pipette to 10 mL ofthe carboxylic acid compound dissolved in DMF at 0.5 mmol/mL at rt. Tothis solution was added 5 mL of DCC in DMF (5.5 mmol), as well as DIEA(15 mmol, 1.62 mL) and this solution was allowed to stir for 30 min.

1 mL of the coupling cocktail described above was added to 0.5 mmol ofan alpha amino ester or alpha amino amide of choice. The reaction wasstirred at rt for 3 hours. The solvent was removed under vacuum. Theresidue was dissolved in 1 mL of EtOAc, and washed with 0.5 N NaOH (3times), then 0.5 N HCl (3 times), and water. The organic layer was driedover MgSO₄, filtered then evaporated under vacuum.

Method Y General Procedure for Amidating a Carboxylic Acid

To an alpha amino amide or alpha amino ester in DMF (0.25 mmol in 200μL) was added1-[(4-chloro-2,5-dimethylbenzenesulfonyl)-4-methyl-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-aceticacid in DMF (0.25 mmol in 200 μL), followed by EDC free amine (0.275mmol) and PS-DIEA (150 mg). The reaction was gently stirred overnight atrt.

The solids were removed by filtration and 3 mL of water was added. Aprecipitate crashed out and was collected by filtration, washed againwith water. The residue was dried on high vacuum.

Method Z General Procedure for Amidating a Carboxylic Acid

A stock solution of1-[(4-chloro-2,5-dimethyl-benzenesulfonyl)-4-methyl-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]-aceticacid in DMF (0.25 mmol/ml) was prepared.

To each solution of alpha amino acid or amide (0.25 mmol/mL) was added 1mL of the above stock solution. To this was added 5 mL of DMF, 35 mg ofPS-DIEA (2 eq) and PS-DCC (530 mg, 2 eq). The reaction vessel was shakenovernight at 150 rpm. Afterwards, each reaction system was filtered toremove solids. 1N HCl (1 mL) was added to each filtrate and the solutionwas evaporated under vacuum. The residue was collected, and analyzed.

The processes set forth in Methods A′ and B′ are illustrated in thefollowing reaction scheme:

Method A′ General Procedure for Forming a Boc Protected Amine[Exemplified by Preparation of α-Cbz-γ-Boc-lysinel

Cbz-protected D-lysine (5 g, 0.016 mol) (Sigma) was dissolved in H₂O andTHF (500 mL, 1:1). To this was first added NaOH (2 eq.) followed bydi-tert-butyl dicarbonate (0.016 mmol). The reaction was stirred at rtovernight. EtOAc (100 mL) was then added and the aqueous layer setaside. The aqueous layer was then acidified to pH 2-3 using 1N HCl andthen extracted with EtOAc (100 mL, 2×). The extracted layers werecombined, washed with brine (100 mL, 2×) and dried over Na₂SO₄. Uponevaporation of the solvent under reduced pressure, the desired materialwas isolated in good yield and used in the next step without furtherpurification.

The carboxylic acid of the Cbz and Boc protected lysine was thenamidated with pyrrolidine in the manner described in Method S above toprovide for1-(R)-1-(pyrrolidin-1-ylcarbonyl)-1-carbobenzyloxyamino-4-butoxycarbonyl-aminobutane.

Method B′ General Procedure for Removing a Cbz Group from a CbzProtected Amine [Exemplified by Preparation of1-(R)-1-(pyrrolidin-1-ylcarbonyl)-1-amino-4-butoxycarbonylaminobutane]

1-(R)-1-(pyrrolidin-1-ylcarbonyl)-1-carbobenzyloxyamino-4-butoxy-carbonylaminobutane(1.5 g, 3.6 mmol) was dissolved in EtOH (30 mL) and then transferred toa Parr hydrogenation bottle. 10% Pd/C was added (100 mg) and the mixturewas hydrogenated at 50 psi for 2 hrs. The reaction mixture was filteredthrough celite and the solvent evaporated under reduced pressure toafford the title compound.

1-(R)-1-(pyrrolidin-1-ylcarbonyl)-1-amino-4-butoxycarbonylaminobutanecan then be reacted with2-(R,S)-1-[(arylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-aceticacid in the manner described in Method S above to provide for theresulting amide,2-(R,S)-[1-(arylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-pyrrolidin-1-ylcarbonyl-4-(t-butoxylcarbonylamino)butyl]acetamide.Removal of the t-butoxylcarbonyl (Boc) group in the manner provided inMethod P above provides for the2-(R,S)-[1-(arylsulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]-N-[1-pyrrolidin-1-ylcarbonyl-4-aminobutyl]acetamide.

The processes set forth in Method C′ is illustrated in the followingreaction scheme:

Method C′ General Procedure for Forming a Heteroaryl Substituent on aPhenyl Group [Exemplified by Preparation of2-(R,S)-[1-(arylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[(1-(R)-1-pyrrolidin-1-ylcarbonyl-2-(4-(N-t-butoxycarbonylpyrrol-2-yl)phenyl)eth-1-yl]acetamide]

(D)-N-t-butoxycarbonyl-p-iodophenylalanine can be prepared by Bocprotecting the commercially available p-iodophenylalanine (Aldrich) inthe manner described above. This compound was then amidated by reactionwith pyrrolidine in the manner described in Method S above provided for1-(R)-[1-(t-butoxycarbonylamino)-1-(pyrrolidin-1-ylcarbonyl)-2-(4-iodophenyl)]ethaneand this amino acid derivative is sometimes referred to herein ascompound 1061.

Removal of the Boc protecting group and coupling with2-(R,S)-[1-(arylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid, in the manner described in Methods O and S above gave the2-(R,S)-[1-(arylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(R)-(1-pyrrolidin-1-ylcarbonyl-2-(4-iodophenyl)eth-1-yl)acetamide.2-(R,S)-2-[1-(arylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(R)-(1-pyrrolidin-1-ylcarbonyl-2-(4-iodophenyl)eth-1-yl)acetamide. (250 mg, 0.34 mmol), was dissolved in dry DME (6 mL) undernitrogen. To this was added Pd(OAc)₂ (0.1 eq), P(O-tolyl)₃ (0.1 eq), 2MNa₂CO₃ (1.7 mL) and 1-(t-butoxycarbonyl)pyrrole-2-boronic acid (2 eq)(Frontier Scientific). The reaction mixture was stirred overnight at 80°C. The solvent was removed under vacuum and EtOAc (20 mL) was added. Theorganic layer was washed with H₂O (10 mL, 2×), brine (10 mL, 1×) anddried over Na₂SO₄. Upon filtration, the solvent was removed under vacuumand the title compound was purified on column chromatography (silicagel) eluted with EtOAc, followed by a prep plate (silica gel) elutedwith EtOAc.

Optionally, the Boc protecting group can then be removed via Method Oabove to provide for2-(R,S)-[1-(arylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[(1-(R)-1-pyrrolidin-1-ylcarbonyl-2-(4-(pyrrol-2-yl)phenyl)eth-1-yl]acetamide.

The processes set forth in Methods D′ and E′ are illustrated in thefollowing reaction scheme:

Method D′ General Procedure for Forming a 2- or 4-Pyridyl Substituent ona Phenyl Group [Exemplified by the Preparation of1-[(R)-1-Pyrrolidin-1-ylcarbonyl-1-amino-2-(4-(2-or4-pyridyl)phenyl]ethane]

1-(R)-[1-(t-butoxycarbonylamino)-1-(pyrrolidin-1-ylcarbonyl)-2-(4-iodophenyl)]ethane(compound 1061) (300 mg, 0.68 mmol), was added to a 50 mL round-bottomflask with CuI (8% mol) in dry DMF (10 mL). The resulting solution wasflushed under nitrogen for 2-3 min. Pd₂dba₃ (2% mol) (Aldrich) and AsPh₃(16% mol) (Aldrich) were weighed together in a small vial to which 1 mLof DMF was added. This solution was added to the reaction mixture and itwas flushed under nitrogen for an additional 2-3 minutes. An oil bathwas heated to 60° C. and the reaction mixture was immersed into it andallowed to thermally equilibrate. The commercially available pyridylstannane (1.15 eq.) (Frontier) was then weighed out into a small vial towhich 1 mL of DMF was added and this solution was then added to theprevious reaction mixture and heated at 60° C. for 6 hours. The solventwas removed under vacuum. The crude residue was dissolved in EtOAc (30mL). The organic layer was washed with brine (10 mL, 2×), and dried overMgSO₄. Upon filtration and evaporation of the solvent under reducedpressure, the crude material was purified on column chromatography(silica gel), eluted with EtOAc-Hexanes 3:2 to afford1-[(R)-1-(pyrrolidin-1-ylcarbonyl)-1-(t-butoxycarbonylamino)-2-(4-(2-or4-pyridyl)phenyl]ethane in good yield.

Subsequent removal of the Boc protecting group with HCl/methanol in themanner described above provides for the title compound as the HCl salt.

Method E′ General Procedure for Forming a 2-Pyrimidinyl Substituent on aPhenyl Group [Exemplified by the Preparation of1-[(R)-1-Pyrrolidin-1-ylcarbonyl-1-amino-2-(4-(2-pyrimidinyl)phenyl]ethane]

1-(R)-[1-(t-butoxycarbonylamino)-1-(pyrrolidin-1-ylcarbonyl)-2-(4-iodophenyl)]ethane(compound 1061)(100 mg, 0.22 mmol), was dissolved in dry MeOH (5 mL) towhich was added KOAc (1.5 eq.) and bis-pinnacolato diboron (1.1 eq.)(Aldrich) and the mixture was flushed under nitrogen for 5 minutes. Thecatalyst, PdCl₂(dppf) (0.03 eq.) (Aldrich), was then added and thereaction was heated at 60° C. overnight. The reaction mixture wasfiltered through Celite and condensed under vacuum. The residue was thentreated with bromopyrimidine (3 eq.) (Aldrich), Na₂CO₃ (5 eq., 0.55 mL)and PdCl₂(dppf) (0.03 eq.) in DMF (1 mL) and stirred at 80° C.overnight. The solvent was removed under vacuum. The crude residue waspurified on column chromatography (silica gel), eluted withEtOAc-Hexanes, 3:2 to afford1-[(R)-1-pyrrolidin-1-ylcarbonyl-1-(t-butoxycarbonylamino)-2-(4-(2-pyrimidinyl)phenyl]ethanein good yield.

Subsequent removal of the Boc protecting group with HCl/methanol in themanner described above provides for the title compound as the HCl salt.

The processes set forth in Methods F′ and G′ are illustrated in thefollowing reaction scheme:

Method F′ General Procedure for the Preparation of1,2,3,6-Tetrahydro-N-Alkylpyridine Derivaties

Boc protected 2-aminoethylpyridine (or the N-methyl analog thereof) (120mg, 0.18 mmol), was dissolved in MeOH/CH₂Cl₂ (2:1) to make a 2.5 Msolution. To this was added MeI (4 eq.) and the mixture was heated in asealed tube for 3.5 h. The solvent was removed under vacuum and theresulting crude mixture was used directly in Method G′ withoutpurification and/or isolation.

Method G′ General Procedure for the Reduction/Hydrogenation of aPyridium Salt

The methyl pyridinium iodide salt produced above, (60 mg, 0.083 mmol),was dissolved in dry MeOH (4 mL) and the resulting mixture cooled to 0°C. Excess NaBH₄ was added and the mixture was allowed to stir for 30min. The solvent was then removed under vacuum and water (5-10 mL) wasadded to the crude product and sonicated for 10 mins. Upon filtration,the solvent was evaporated to provide for Boc protected2-aminoethyl-1,2,3,6-tetrahydropyridine in good yields.

If desired, the remaining unsaturated bond in the Boc protected2-aminoethyl-1,2,3,6-tetrahydropyridine can be hydrogenated withhydrogen/PtO₂ maintained at about 35 psi.

The Boc protecting group of the saturated or unsaturated compound canthen be removed by conventional methods (e.g., HCl/methanol).

The process set forth in Method H′ is illustrated in the followingreaction scheme:

Method H′ General Procedure for Preparing Libraries of DifferentArylsulfonyl Groups

0.33 mmol of2-(R,S)-[3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamidedissolved in 1 mL of pyridine, was added to 0.50 mmol of each separatesulfonyl chloride, dissolved in 1.5 mL of pyridine at 0° C., in theproposed library set. All reactions were prepared in 1-dram reactionvials and placed on a J-Kem Orbit Shaker. The reactions were thenbrought up to rt and left for 16 h. Afterwards, LC-MS analysis for eachproduct mixture was completed on an Agilent 1050 series HPLC coupled toa Thermo-Finnigan Mass Spectrometer, utilizing a 6-minute 5%-100%CH₃CN:H₂O gradient with 0.05% TFA on a Phenomenex 50×2.00 mm, 5 microncolumn. Products were purified via the Varian Pro Star Preparative HPLC,using a 17-minute 10%-100% CH₃CN:H₂O gradient with 0.1% TFA on aPhenomenex 60×21.20 mm, 50 micron column.

The process set forth in Method I′ is illustrated in the followingreaction scheme:

Method I′ General Procedure for Converting an Aniline Amino Group to anAmide in a Library Manner [Exemplified by the Preparation of a Libraryof2-(R,S)-[1-(4-chloro-2,5-dimethylphenylsulfinyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-((4-RC(O)NH—)phenyl)eth-1-yl]acetamide]

2-(R,S)-[1-(4-Chloro-2,5-dimethylphenylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-((4-amino)phenyl)eth-1-yl]acetamide(20.0 mg, 0.038 mmole) was dissolved in dioxane (600 μL) and treatedwith PS-DIEA (31.0 mg, 0.0114 mmole). After shaking at rt for 15minutes, each respective acid chloride (RC(O)Cl) (0.038 mmole) wasadded. In a few instances, generation of the acid chloride from thecarboxylic acid was necessary prior to this acylation step. Thisconversion was accomplished by dissolving the acid (0.076 mmole) in

CH₂Cl₂ (500 μL), adding oxalyl chloride (9.0 μL) plus a catalytic amountof DMF and allowing to shake at rt for 3 h. The solvent was subsequentlyremoved by reduced pressure, THF (500 μL) was added and removed by thesame means, to ensure complete removal of excess oxalyl chloride. Theisolated acid chloride was then used in the acylation procedure, withoutfurther characterization.

Following addition of each acid chloride to a separate reaction vesselcontaining the2-(R,S)-[1-(4-chloro-2,5-dimethylphenylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-((4-amino)phenyl)eth-1-yl]acetamide,the reaction mixtures were stirred (shaken) at rt for 18 h. Confirmationof acylation and product purity were determined by LC-MS. A portion ofthe reactions exhibited incomplete conversion, therefore, additionalacid chloride (0.038 mmole) and Et₃N (100 μL) were added. Thesereactions were then allowed to shake at 50° C. for 4 h, followed by 8 hof shaking at rt. The resin was removed by filtration, and the sampleswere purified by prep HPLC, using a Phenomenex 60×21.20 mm, 50-microncolumn; 16 minute gradient, 0-100% CH₃CN to H₂O, with 0.1% TFA. Thepurity of each isolated product was confirmed by LC-MS.

The process set forth in Method J′ is illustrated in the followingreaction scheme:

Method J′ General Procedure for Converting the Amino Nitrogen ofPiperidine to an Amide in a Library Manner [Exemplified by thePreparation of a Library of2-(R,S)-[1-(4-chloro-2,5-dimethylphenylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(1-RC(O)-piperidin-4-yl)eth-1[-yl]acetamide]

Into separate vials,2-(R,S)-[1-(4-chloro-2,5-dimethylphenylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(piperidin-4-yl)eth-1-yl]acetamide(25.0 mg, 0.04825 mmole) was dissolved in CH₂Cl₂ (600 μL) and treatedwith PS-DIEA (39.4 mg, 0.0145 mmole). After shaking the respective vialsat rt for 15 min., each respective acid chloride (0.0531 mmole) wasadded to a separate vial. Similar to the acylation set forth in MethodI′ above, there were a few cases in which the acid chloride requiredconversion from the carboxylic acid prior to this acylation. Theconversion was completed as mentioned in the acylation set forth inMethod I′ above.

Following the addition of the acid chlorides, the reactions were allowedto shake at rt for 18 h. Confirmation of acylation and determination ofpurity was analyzed by LC-MS. A portion of the library exhibitedincomplete conversion, therefore, additional acid chloride (0.0531mmole) and TEA (20 μL) were added. These reactions were allowed to shakeat 70° C. for 4 h, adding additional CH₂Cl₂ as necessary, followed byshaking at rt for an additional 8 h. The resin was removed byfiltration, and the samples were purified by prep HPLC using aPhenomenex 60×21.20 mm, 50-micron column; 16 minute gradient, 0-100%CH₃CN to H₂O, with 0.1% TFA. The purity of each isolated product wasconfirmed by LC-MS.

The processes set forth in Method K′ are illustrated in the followingreaction scheme:

Method K′ General Procedure for Preparing N-(pyrid-2-yl)piperidineCompounds [Exemplified by the Preparation of2-[1-(pyrid-2-yl)piperidin-4-yl]ethyl]amine]

Step A: Synthesis of N-t-butoxycarbonyl 2-(pyrid-2-yl)ethylamine

4-Aminoethylpyridine (5.0 g, 40 mmol) and di-t-butyl dicarbonate (8.9 g,40 mmol) were dissolved in CH₂Cl₂ (50 mL) and the resulting solution wasstirred at rt for overnight. Solvent was removed under reduced pressureto afford N-t-butoxycarbonyl 2-(pyrid-2-yl)ethylamine as a reddishliquid (9.1 g, 100%).

Step B: Synthesis of N-t-butoxycarbonyl 2-(piperidin-2-yl)ethylamine

The product from step A was mixed with PtO₂ (640 mg) in HOAc (30 mL) andhydrogenation was carried out at 58 psi on a Parr apparatus forovernight. Catalyst was removed and solvent was evaporated under reducedpressure to give N-t-butoxycarbonyl 2-(piperidin-2-yl)ethylamine as ablack liquid.

Step C: Synthesis of N-t-butoxycarbonyl2-[1-(pyrid-2-yl)piperidin-4-yl]ethylamine

To a solution of N-t-butoxycarbonyl 2-(piperidin-2-yl)ethylamine (8.1 g)and DIEA (14.1 mL) in CH₃CN (29 mL) was added 2-fluoropyridine (3.5 mL)and the resulting mixture was heated in a sealed-tube at 100° C. forthree days. Solvent was removed and the crude product was purified viacolumn chromatography (20% EtOAc/hexane) to afford 3.9 g ofN-t-butoxycarbonyl 2-[1-(pyrid-2-yl)piperidin-4-yl]ethylamine. ¹H NMR(CDCl₃) δ=8.16 (dd, J=1.8, 5.0 Hz, 1H), 7.44-7.38 (m, 1H), 6.61 (d,J=8.7 Hz, 1H), 6.53 (dd, J=5.0, 7.2, 1H), 4.58 (bs, 1H), 4.23 (d, J=12.6Hz, 2H), 3.15 (q, J=6.6 Hz, 2H), 2.76 (dt, J=2.7, 12.6 Hz, 2H), 1.75 (d,J=12.6 Hz, 2H), 1.55-1.35 (m, 1H), 1.28-1.15 (m, 3H);

MS (ES) m/e: m/z (EI⁺) 306 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column) R_(t)=2.27 min.

Step D: Synthesis of 2-[1-(pyrid-2-yl)piperidin-4-yl]ethylamine

To a solution of N-t-butoxycarbonyl2-[1-(pyrid-2-yl)piperidin-4-yl]ethylamine (3.9 g) in EtOAc (15 mL) wasbubbled HCl (g) for 15 min. The suspension was then stirred underpositive pressure (N2) for 30 min. Solvent was removed under vacuum toafford the 2-[1-(pyrid-2-yl)piperidin-4-yl]ethylamine (pure) as thehydrochloride salt (white solid) (3.4 g, 98%).

The processes set forth in Method L′ are illustrated in the followingreaction scheme:

Method L′ General Procedure for the Preparation of CarbamoyloxySubstituted Phenylethyl Amine Compounds [Exemplified by the Preparationof 2-[4-(N′,N′-dimethylaminocarbonyloxy)phenyl]ethylamine]

Step A: Synthesis of N-t-butoxycarbonyloxy 2-(4-hydroxyphenyl)ethylamine

The amine group of 2-(4-hydroxyphenyl)ethylamine was protected with aBoc protecting group in the manner described above in Method K′ toprovide for N-t-butoxycarbonyloxy 2-(4-hydroxyphenyl)ethylamine.

Step B: Synthesis of N-t-butoxycarbonyloxy2-[4-(N′,N′-dimethylaminocarbonyloxy)phenyl]ethylamine

N-t-butoxycarbonyloxy 2-(4-hydroxyphenyl)ethylamine (2.53 g, 10.7 mmol),Et₃N (2.96 mL, 2 eq.), a catalytic amount of DMAP (131 mg) anddimethylcarbamyl chloride (2.0 mL, 2 eq) were mixed in CH₂Cl₂ at 0° C.The resulting mixture was stirred for overnight. EtOAc was added todilute the reaction mixture and then was washed with 1N HCl, sat.Na₂CO₃and brine. Solvent was removed under reduced pressure to give puret-butoxycarbonyloxy2-[4-(N′,N′-dimethylaminocarbonyloxy)phenyl]ethylamine a colorlesssolid.

Step C:Synthesis of2-[4-(N′,N′-dimethylaminocarbonyl-oxy)phenyl]ethylamine

The Boc protecting group on the t-Butoxycarbonyloxy2-[4-(N′,N′-dimethylaminocarbonyloxy)phenyl]ethylamine was removed in amanner similar to that set forth in Step D, of Method K′ to provide forthe title compound a white solid, and this compound was used “as is” inthe next step.

The processes set forth in Method M′ are illustrated in the followingreaction scheme:

Method M′ General Procedure for Converting2-[4-(N,N-dimethylaminophenyl]ethanol to2-[4-(N′,N′-dimethylaminophenyl]ethylamine

Step A: Synthesis of2-[2-(4-N,N-dimethylaminophenyl)-ethyl]isoindole-1,3-dione

2-[4-(N,N-dimethylaminophenyl]ethanol (2.05 g, 17.4 mmol), phthalimide(2.19 g, 14.9 mmol) and PPh₃ (3.93 g, 14.9 mmol) (Aldrich) were mixed in100 mL of THF maintained at 0° C. The mixture was then treated with DIAD(2.68 mL) (Aldrich) which was added dropwise. After stirring overnight,the solvent was removed under reduced pressure to give a pale yellowsolid. The solid was triturated with EtOAc three times. The combinedEtOAc layers were treated with gaseous HCl to precipitate the product,and the desired product was isolated through filtration.

Step B: Synthesis of 2-[4-(N′,N′-dimethylaminophenyl]ethylamine

2-[2-(4-N,N-dimethylaminophenyl)-ethyl]-isoindole-1,3-dione (606 mg,1.84 mmol) and hydrazine hydrate (30%, 0.64 mL) in ethanol was heated at65° C. for 5 h. The precipitate was removed via filtration. The filtratewas concentrated to give the title compound as a white solid. Thisproduct was used in the next step without further purification.

The processes set forth in Method N′ are illustrated in the followingreaction scheme:

Method N′ General Procedure for Preparing2-[(1-Pyrimidin-2-yl)piperidin-4-yl]-ethylamine

Step A: Synthesis of N-t-butoxycarbonyloxy2-[1-(pyrimidin-2-yl)piperidin-4-yl]-ethylamine

N-t-butoxycarbonyloxy 2-(piperidin-4-yl)-ethylamine (prepared per MethodK′ above), DIEA (0.75 mL) and 2-bromopyrimidine (204 mg) (Aldrich) inacetonitrile (5 mL) were heated under reflux overnight. The solvent wasremoved under reduced pressure and the black liquid was subjected to acolumn chromatography, eluted with 1:1 EtOAc/hexanes, to give pureN-t-butoxy-carbonyloxy 2-[1-(pyrimidin-2-yl)piperidin-4-yl]-ethylamineas a pale yellow oil. ¹H NMR (CDCl₃) δ=8.21 (d, J=5.1 Hz, 2H), 6.36 (t,J=5.1 Hz, 1H), 4.64 (d, J=13.8 Hz, 2H), 3.14-3.07 (m, 2H), 2.76 (dt,J=2.7, 13.2 Hz, 1H), 1.69 (d, J=13.8 Hz, 1H), 1.57-1.30 (m, 1H),1.20-1.03 (m, 3H);

MS: m/z (EI⁺) 307 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column) R_(t)=2.63 min.

Step B: Synthesis of 2-[(1-pyrimidin-2-yl)piperidin-4-yl]-ethylamine

The Boc protecting group on N-t-butoxy-carbonyloxy2-[1-(pyrimidin-2-yl)piperidin-4-yl]-ethylamine was removed using Step Dof Method K′ to afford the title compound.

The processes set forth in Method O′ are illustrated in the followingreaction scheme:

Method O′ General Procedure for Preparing N-(pyrid-4-yl)piperidineCompounds

Step A: Synthesis of N-t-butoxycarbonyloxy2-[1-(pyrid-4-yl)piperidin-4-yl]-ethylamine

N-t-butoxycarbonyloxy 2-(piperidin-4-yl)-ethylamine (prepared per MethodK′ above) (14.4 g, 50 mmol), 4-chloropyridine HCl (1.0 eq., 8.0 g), TEA(2.2 eq.) were mixed in ethanol, and maintained under reflux overnight.The desired compound, N-t-butoxycarbonyloxy2-[1-(pyrid-4-yl)piperidin-4-yl]ethylamine, was isolated by columnchromato-graphy, (silica gel) eluted with EtOAc and carried in the nextstep.

Step B: Synthesis of 2-[1-(pyrid-4-yl)piperidin-4-yl]-ethylamine

The Boc protecting group on N-t-butoxycarbonyloxy2-[1-(pyrid-4-yl)piperidin-4-yl]-ethylamine was then removed using usingMethod K′, Step D, to provide the title compound.

Method P′ is the same as Methods F′ and G′. Any reaction referencingMethod P′ in the examples below, may be accomplished by Method F′ or G′.

The processes set forth in Method Q′ are illustrated in the followingreaction scheme:

Method Q′

To a solution of the starting aniline (100 mg; 0.19 mmol) in drypyridine (5 mL), was added acetic anhydride (20 μL). The mixture wasstirred at rt overnight. Water (3 mL) was added to the mixture and theproduct was precipitated from the solution.

The processes set forth in Method R′ are illustrated in the followingreaction scheme:

Method R′ General Procedure for Converting the Amino Nitrogen ofPiperidine to an Amide [Exemplified by the Preparation of a Library of2-(R,S)-[1-(4-chloro-2,5-dimethylphenylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl-N-[2-(1-RC(O)-piperdin-4-yl)eth-1-yl]acetamide]

2-(R,S)-[1-(4-chloro-2,5-dimethylphenylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(piperidin-4-yl)eth-1-yl]acetamide(25.0 mg, 0.04825 mmol) was dissolved in CH₂Cl₂ (600 μL) and treatedwith DIEA (2.0 eq.). After shaking at rt for 15 minutes, each respectiveacid chloride (0.0531 mmole) was added. The reaction was stirred at rtovernight. The organic layer was washed with brine, dried over MgSO₄.Upon filtration over celite, the crude material was purified over columnchromatography (silica gel) eluted with CHCl₃:MeOH 9:1.

Method S′ General Procedure for Amidating a Carboxylic Acid

To a solution of the carboxylic acid (916 mg) in dry pyridine (5 mL), at−20° C. was added the amine hydrochloride salt piece (280 mg) inpyridine (5 mL), followed by POCl₃ (0.11 ml). The mixture was stirred atthis temperature for 1.5 hours. The reaction was then quenched with ice.The mixture was diluted with water and was extracted with EtOAc. Theorganic solvent was concentrated to give the crude product, which waspurified through a column chromatography (silica gel) system, elutedwith EtOAc/hexanes to give the desired pure product.

Method T′ General Procedure for Conversion of a Vinylpyridine Group to a2-Aminoethylpyridine Group [examplified by the preparation of2-N-ethyl]-eth-1-yl-pyridine]

4-Vinyl pyridine (1.6 mL; 15 mmol) was dissolved in acetic acid (12.5mmol; 0.72 mL) and ethylamine (12.5 mmol). The reaction mixture wasrefluxed for 6 hours. The solvent was evaporated under reduced pressure.A solid was evaporated. EtOAc was added as well as saturated NaHCO₃. Theorganic layer was isolated, dried over MgSO₄. The solvent was removedunder reduced pressure. The desired material was isolated as a foam.

H¹ (CDCl₃) 8.5 (m, 2H); 7.1 (m, 2H); 2.9 (m, 2H); 2.8 (m, 2H); 2.7 (m,2H); 1.1 (m, 3H).

Method U′ General Procedure for Amidating a Carboxylic Acid

A mixture of the amine hydrochloride or trifluoroacetate salt,R,S-[1-(4-chloro-2,5-dimethyl-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]-aceticacid, and triethyl amine (3.0 equ) in 5 mL of acetonitrile, with a smallamount of DMF added for solubility, was treated with HATU (1.0 eq). Theresulting homogeneous solution was stirred at room temperature for 2hours then concentrated and diluted with a mixture of chlororform andisopropanol (3:1). The organic layer was washed with saturated aqueousodium bicarbonate solution and brine, dried in vacuo, and concentrated.The residue was purified by HPLC to give the title compound

The process set forth in Method V′ is illustrated in the followingscheme

Method V′ Preparation of 2-(2-methylpyridin-2-yl)ethylamine

Step A: Synthesis of (2-Methyl-pyridin-4-yl)-acetic acid methyl ester(and bis adduct)

A solution of diisopropyl amine (7.52 mL, 53.66 mmol) in 30 mL of THFwas cooled to −78° C. and a solution of 2.5 M n-butyllithium in hexanes(21.46 mL, 53.66 mmol) was added slowly. The solution was allowed towarm to room temperature and 2,4-dimethyl-pyridine (5.39 mL, 46.66 mmol)in 5 mL of THF was added dropwise.

The reaction was stirred for 4 hours at room temperature thentransferred via an addition funnel to a room temperature solution ofdimethyl carbonate (3.93 mL, 46.66 mmol) in 30 mL of THF. The resultingsolution was stirred overnight and quenched with saturated aqueousammonium chloride. The mixture was extracted several times with ethylacetate and the combined organic layers were dried over anhydrous sodiumsulfate. Flash chromatography on silica using a hexane/ethyl acetategradient (20-60%) afforded 2.29 g of the title compound as a thick oil.MS(ES): m/e (EI*) 166.1 [M+H].

Step B: Synthesis of (2-Methyl-pyridin-4-yl)-acetic acid ethyl ester

The mixture of (2-methyl-pyridin-4-yl)-acetic acid methyl ester and thebis adduct (20 g) was dissolved in concentrated hydrochloric acid andheated to reflux for 1 hour. The solution was cooled, diluted withtoluene, and concentrated in vacuo to give the crude acid. The acid wasdissolved in ethanol, treated with a catalytic amount of sulfuric acid,and heated to reflux for 3 h. The solution was cooled to roomtemperature and concentrated in vacuo. The residue was dissolved inethyl acetate and washed with saturated aqueous sodium chloridesolution. The mixture was filtered and the filtrate concentrated to give14 g of the title compound as a crude oil. MS(ES): m/e (EI*) 180.1 [M+H]

Step C: Synthesis of 2-(2-Methyl-pyridin-4-yl)-ethanol

A solution of (2-methyl-pyridin-4-yl)-acetic acid ethyl ester (3.75 g,20.2 mmol) in 100 mL of THF was cooled in an ice bath and a 1.0Msolution of LAH in THF was added (15.7 mL, 15.7 mmol). The reactionmixture was allowed to warm to room temperature and stirred overnight.The mixture was cooled in an ice bath and quenched with the successiveaddition of water, 15% aqueous sodium hydroxide solution and additionalwater. The resulting mixture was stirred at room temperature for I hourthen dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated to give 2.8 g of the title compound as a light brown oil.MS(ES): m/e (EI*) 138.1 [M+H]

Step D: Synthesis of2-[2-(2-methyl-pyridin-4-yl)ethyl]isoindole-1,3-dione

A solution of triphenylphosphine (3.18 g, 12.12 mmol) anddiisopropylazodicarbocylate (2.39 μL, 12.12 mmol) in 10 mL of THF wasstirred at 0° C. for 30 min and combined with a solution of2-(2-methyl-pyridin-4-yl)-ethanol and phthalimide (1.33 g, 9.7 mmol) in10 mL of THF. The resulting solution was stirred overnight at roomtemperature and concentrated in vacuo. The residue was dissolved inethyl acetate and the organic layer was washed successively withsaturated aqueous sodium bicarbonate and saturated aqueous sodiumchloride solutions. The organic layer was dried over sodium sulfate andconcentrated in vacuo. Flash chromatography on silica using adichloromethane/methanol gradient (2-10%) gave 2.5 g of the titleproduct. MS(ES): m/e (EI*) 267.1 [M+H]

Step E: Synthesis of 2-(2-Methyl-pyridin-4-yl)-ethylamine

A solution of 2-[2-(2-methyl-pyridin-4-yl)-ethyl]-isoindole-1,3-dione(2.58 g, 9.69 mmol) in 20 mL of ethanol was heated to reflux for 5hours. The reaction was allowed to cool and stirred overnight. Theresulting slurry was filtered and the filtrate was concentrated. Theresidue was dissolved in ethyl acetate and extracted several times with10% aqueous hydrogen chloride solution. The aqueous layers were combinedand neutralized with sodium carbonate and extracted with a mixture ofchloroform and isopropanol (3:1). The organic layer was dried overanhydrous sodium sulfate, filtered, and concentrated to give the tilecompound as a clear colorless oil. MS(ES): m/e (EI*) 137.1 [M+H]

The reaction set forth in Method W is exemplified below

Method W′ Preparation of N1-(1H-Benzoimidazol-2-yl)-ethane-1,2-diamine

A mixture of 2-chloro-1H-benzoimidazole (1 g) in 4 mL ofethane-1,2-diamine was heated to 10° C. for several hours until completeby HPLC. The reaction was allowed to cool and diluted with a mixture ofchlororform and isopropanol (3:1). The organic phase was washed withwater then dried and concentrated to give 216 mg of product as a solidwhich was used in the next step without further purification. MS(ES):m/e (EI*) 177.1 [M+H]

The process set forth in Method X′ is illustrated below

Method X′ Preparation of 2-(4-pyrdin-2-yl-phenyl)-ethylamine

Step A: Synthesis of [2-(4-Bromo-phenyl)-ethyl]-carbamic acid tert-butylester

2-(4-Bromo-phenyl-ethylamine was protected with a Boc protecting groupin the manner described in step A of Method K′ to provide[2-(4-Bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester, inquantitative yields. The compound was used as is in the next step.

Step B: Synthesis of [2-(4-Pyridin-2-yl-phenyl)-ethyl]-carbamic acidtert-butyl ester

[2-(4-Bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester (1.5 g, 4.99mmol) was dissolved in toluene (0.2 M) in a 100 mL round-bottom flask.To this was added LiCl (10.6 mg, 0.25 mmol, 0.05 eq) and the resultingsolution was flushed under nitrogen for 2-3 minutes. PdCl₂(PPh₃)₂ (175.4mg, 0.25 mmol, 0.05 eq) was added to the reaction mixture and thesolution was again flushed under nitrogen for 2-3 minutes.2-Tributylstannanyl-pyridine, from Frontier (1.84 g, 4.99 mmol, 1 eq)was added last and the reaction mixture was heated to 110° C. overnight.The solvent was removed under vacuum. The crude material was purified oncolumn chromatography (silica gel), and eluted with EtOAc-Hexanes 15:85to afford [2-(4-Pyridin-2-yl-phenyl)-ethyl]-carbamic acid tert-butylester in good yield.

Step C: Synthesis of 2-(4-Pyridin-2-yl-phenyl)-ethylamine

[2-(4-Pyridin-2-yl-phenyl)-ethyl]-carbamic acid tert-butyl ester wasdissolved in a 1:1 mixture of trifluroacetic acid:dichloromethane. Thereaction mixture was stirred at room temperature overnight after whichthe product was recovered upon solvent removal. The TFA salt was used inthe next step without further purification.The process set forth in Method Y′ is outlined below

Method Y′ Preparation of 4-(pyridin-4-yl)but-3-lamine

Step A: Synthesis of but-3-ynyl-carbamic acid tert-butyl ester

The procedure described in Taylor, Tetrahedron. 1987, Volume 43, page5145 was followed. This reference is incorporated by reference herein inits entirey.

Step B: But-3-ynyl-carbamic acid tert-butyl ester was reacted with

4-bromo pyridine (Aldrich) using a catalytic amount of PdCl₂(PPh3)₂, andCuI, according to the procedure reported by Glase, S. A et al. in J.Med. Chem. 1996, Volume 39, pages 3179-3187.

Step C: Deprotection took place using neat TFA. Upon evaporation of thesolvent under reduced pressure, an oil was isolated. HPLC(acetonitrile-water-0.1% TFA) R_(t)=0.79 mn. MS (ES): m/e 147 (M+H).

Example 1 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-methylenecarbonyl-{[4-(2-(N-t-butoxycarbonylamino)ethyl)piperidin-1-yl]}

The title compound was preparedfrom[2-(R,S)-1-(4-chloro-2,5-dimethyl-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid, and 4-(2-(N-t-butoxycarbonyl-amino)ethyl)piperidine using MethodI.

¹H NMR (DMSO-d₆): δ=0.77-1.59(m, 7H), 1.40(s, 9H), 1.95(s, 3H), 2.01(s,3H), 2.20-2.52(m, 2H), 2.70-2.92 (m, 4H), 3.47(brd, 1H), 3.30(brd, 1H),4.83(m, 1H), 6.73-7.49(m, 6H)10.53(s, 1H);

MS (ES): m/e 643 (M+Na);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=6.35 min.

Example 2 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-methylenecarbonyl-[4-(2-aminoethyl)]piperidin-1-yl]

The title compound was prepared from2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]methylene-carbonyl-{4-(2-(N-t-butoxycarbonyl-amino)ethyl)piperidin-1-yl}using Method P in ethyl acetate. The desired material was isolated as anHCl salt.

¹H NMR (DMSO-d₆): δ=0.84-1.60 (m, 7H), 2.00(s, 3H), 2.20(s, 3H),2.36-2.47(m, 2H), 2.75-2.83(m, 2H), 3.48-3.52(br d, 1H), 4.28-4.31(brd,1H), 4.81(m, 1H), 6.84-7.47(m, 6H), 8.05(brs, 2H, NH₂)10.56(s, 1H);

MS (ES): m/e 520.1 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=3.48 min.

Example 3 Preparation of[2-(R,S)-1-(4-Chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-S-(p-tolyl)thioaceticacid ester

The title compound was prepared from[2-(R,S)-1-(4-chloro-2,5-dimethyl-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and p-thiocresol using Method I.

¹H NMR (DMSO-d₆): δ=1.97 (s, 3H), 2,21 (s, 3H), 2.32 (s, 3H), 2.64-2.89(m, 2H), 4.85 (m, 1H), 6.82-7.5 (m, 8H), 10.63 (s, 1H);

MS (ES): m/e 516.1 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column) R_(t)=8.034 min.

Example 4 Preparation of2-[2-(R,S)-1-(2,3-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-methyl-N-[2-(N-methylpiperidin-4-yl)eth-1-yl}acetamide

The title compound was prepared from2-[2-(R,S)-1-(2,3-dichloro-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and N-methyl-(2-(N-methyl-piperidin-4-yl)eth-1-yl)amine usingMethod I and purified by preparative HPLC.

¹H NMR (DMSO-d₆): δ=1.06-1.91 (m, 7H), 2.32-2.60 (m, 2H), 2.75-3.40 (m,6H), 2.44 (s, 3H), 2.47 (s, 3H), 4.84 (dd, 1H, J=3.3 Hz,) 4.96 (dd, 1H,J=3.3 Hz), 6.85-7.94 (m, 8H), 10.71(s, 1H, NH), 10.76 (s, 1H, NH),

MS (ES): m/e 548.1 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=2.53 min.

Preparation of2-[2-(R)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(pyridin-4-yl)piperidin-4-yl]eth-1-yl}acetamide

The title compound was prepared from[2-(R)-1-(4-chloro-2,5-dimethyl-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and 2-[N-(pyridin-4-yl)piperidin-4-yl]ethylamine using Method I.

¹H NMR (DMSO-d₆): δ=1.03-1.80 (m, 7H), 1.98 (s, 3H), 2.20 (s, 3H),2.09-2.24 (m, 2H), 2.75-3.13 (m, 4H), 3.88 (brd, 2H), 4.85 (dd, 1H,J=5.1 Hz), 6.76 (brd, 2H), 6.78-7.47 (m, 6H), 7.85 (brt, 1H, NH), 8.08(brd, 2H);

MS (ES): m/e 596.2(M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=2.66 min.

Example 6 Preparation of2-[2-(S-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(pyrid-4-yl)]piperidin-4-yl}acetamide

The title compound was prepared from[2-(S)-1-(4-chloro-2,5-dimethyl-benzene-sulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and 2-[N-(pyridin-4-yl)piperidin-4-yl]ethylamine using Method I.

¹H NMR (DMSO-d₆): δ=1.03-1.80 (m, 7H), 1.97 (s, 3H), 2.19 (s, 3H),2.10-2.30 (m, 2H), 2.75-3.12 (m, 4H), 3.87 (brd, 2H), 6.75 (brd, 2H,Py), 6.78-7.41 (m, 6H), 7.83 (brt, 1H, NH), 8.05 (brd, 2H, Py), 10.42(s, 1H, NH);

MS (ES): m/e 597(M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=2.65 min.

Example 7 Preparation of2-[2-(R,S)-1-(3-chloro-2-methylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-benzylacetamide

The title compound was obtained from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]-N-benzylacetamideusing Method G and 2-methyl-3-chloro benzene sulfonyl chloride.

¹H NMR (300 MHz, CD₃OD) δ=8.42 (1H, t), 7.77 (1H, d, J=8.7 Hz), 7.67(1H, d, J=8.1 Hz), 7.33 (8H, m), 7.11 (1H, m), 6.87 (1H, d, J=7.8 Hz),4.89 (1H, q), 4.32 (1H, dd), 4.05 (1H, dd), 2.35 (2H, m), 2.18 (3H, s);

¹³C NMR (300 MHz, CD₃OD) ppm 167.12, 166.48, 139.29, 137.47, 136.60,135.44, 135.01, 133.84, 133.71, 129.64, 128.91, 128.53, 128.35, 127.90,127.47, 127.10, 123.25, 121.23, 116.21, 56.17, 55.23, 16.56;

MS (ES): m/e 484.1 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=5.20 min.

Example 8 Preparation of2-[2-(R,S)-1-(2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-benzylacetamide

The title compound was obtained from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]-N-benzylacetamideusing Method G, and 2,5-dimethylbenzene sulfonyl chloride.

¹H NMR (300 MHz, CD₃OD) δ=10.42 (1H, s), 8.40 (1H, t), 7.34 (9H, m),7.17 (1H, d, J=8.4 Hz), 7.08 (1H, t), 6.81 (1H, d, J=7.8 Hz), 4.95 (1H,q), 4.32 (1H, dd), 4.13 (1H, dd), 2.33 (2H, m), 2.22 (3H, s), 2.05 (3H,s);

¹³C NMR (300 MHz, CD₃OD) ppm 167.32, 166.63, 139.36, 136.28, 135.06,134.67, 134.52, 133.73, 133.01, 130.33, 128.52, 128.31, 127.47, 127.07,122.99, 121.65, 116.09, 56.21, 42.47, 36.77, 20.54, 19.67;

MS (ES): m/e 464 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=5.25 min.

Example 9 Preparation of2-[2-(R,S)-1-(2-methylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-benzylacetamide

The title compound was obtained from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]-N-benzylacetamide,using Method G, and 2-methylbenzene sulfonyl chloride.

¹H NMR (300 MHz, CD₃OD) δ=10.46 (1H, s), 8.40 (1H, t), 7.52 (2H, m),7.29 (9H, m), 7.10 (1H, m), 6.79 (1H, q), 4.99 (1H, m), 4.35 (1H, m),4.14 (1H, dd), 2.34 (3H, s), 2.28 (2H, m);

¹³C NMR (300 MHz, CD₃OD) ppm 167.37, 167.30, 166.70, 144.56, 139.36,137.69, 135.52, 134.16, 133.66, 133.19, 130.21, 129.96, 128.52, 128.17,127.48, 127.41, 127.07, 126.97, 126.88, 123.05, 121.66, 116.17, 60.08,56.40, 56.11, 42.47, 36.76, 21.36, 21.09, 20.12, 14.41;

MS (ES): m/e 450.1 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=4.85 min.

Example 10 Preparation of2-[2-(S)-1-(benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamide

The title material was obtained from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]-N-(pyrid-4-yl)ethylacetamideusing Method G and benzene sulfonyl chloride.

¹H NMR (CD₃OD) δ=10.31 (1H, s), 8.48 (2H, q), 8.01 (1H, t), 7.64 (1H,t), 7.45 (3H, m), 7.25 (5H, m), 7.10 (1H, m), 6.75 (1H, d, J=9.0 Hz),4.98 (1H, q), 2.70 (2H, t), 2.21 (2H, m);

¹³C NMR (¹H) δ=167.32, 166.18, 149.73, 148.73, 136.82, 134.16, 133.29,129.55, 128.60, 128.21, 126.89, 124.56, 123.09, 116.13, 56.30, 36.81,34.35;

MS m/z (M+H) 451.1;

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=1.41 min.

Example 11 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-6,7-dimethylquinoxalin-2-yl]-N-benzylacetamide

The title material was prepared from 4,5-dimethyl-1,2-phenylenediamineusing Method F, followed by Method H using 2,5-dimethyl-4-chlorobenzenesulfonyl chloride.

¹H NMR (DMSO-d₆) δ=2.0-2.5 (dd, m, s 14H), 4.15 (dd, J=14.5 Hz, 1H), 4.3(dd, J=14.5 Hz, 1H), 4.89 (dd, J=4.5 Hz, 1H), 7.14-7.49 (m, ArH, 8H),8.36 (t, 1H, NH), 10.35 (s, 1H, NH);

MS (ES): m/e 527.3 (M+H), 550.3 (M+Na).

Example 12 Preparation of 2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(methoxycarbonyl)-2-(N-methylpiperidin-4-yl)eth-1-yl]acetamide

The title compound was obtained as a single diastereomer byrecrystallization of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzene-sulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(methoxycarbonyl)-2-(N-methylpiperidin-4-yl)eth-1-yl]acetamidewith ethyl acetate.

¹H NMR (DMSO-d₆) δ=1.06-2.40 (brm, 10H), 1.99(s, 3H), 2.22(s, 3H),2.75(br. d, 2H), 3.60(s, 3H), 4.30(m, 1H), 4.82(t, J=6 Hz, 1H),6.79-7.42(m, Ar—H, 6H), 8.32(d, J=7.5 Hz, 1H);

MS (ES): m/e: 590.1 (M+H), 613(M+Na);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=4.01 min.

Example 13 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]-N-iso-propylacetamide

Iso-propyl-(2-pyridin-4-yl-ethyl)-amine, obtained from 4-vinylpyridineusing Method U, and was subsequently reacted with2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid using Method I to afford the title material.

¹H NMR (DMSO-d₆) δ=0.79-1.08 (m, 6H), 1.90 (s, 3H), 2.18 (s, 3H),2.30-2.70 (brm, 4H), 2.90-3.28(m, 4H), 3.74 (m, 1H), 4.28(m, 1H),4.93(m, 1H), 6.71-7.46(m, 8H), 8.23(d, 2H), 8.43(d, 2H);

MS (ES): m/e 556.1 (M+H), 579 (M+Na);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column) R_(t)=3.94 min.

Example 14 Preparation of2-[2-(S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-methylenecarbonyl{[1-(pyridin-2-yl)]-4-piperazin-4-yl}

2-[2-(R,S)-1-(4-Chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]aceticacid was reacted with 1-pyridin-2-yl-piperazine using Method I to affordthe title material as a solid.

¹H NMR (DMSO-d₆) δ=2.02 (s, 3H), 2.21 (s, 3H), 2.53 (m, 2H), 3.30-3.48(m, 8H), 4.89 (m, 1H), 6.62-8.75 (m, 10H, Ar—H), 10.55 (s, 1H, NH);

MS (ES): m/e: 555 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=3.77 min.

Example 15 Preparationof2-[2-(R,S)-1-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)-eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(pyrid-4-yl)ethylacetamideand 4-methoxy 2,3,6-trimethylbenzene sulfonyl chloride using Method G.

¹H NMR (DMSO-d₆) δ=10.30 (1H, s), 8.44 (2H, d, J=6.0 Hz), 7.95 (1H, t),7.22 (3H, m), 6.95 (3H, m), 6.84 (1H, s), 4.71 (1H, q), 3.86 (3H, s),2.66 (2H, t), 2.38 (3H, s), 2.29 (3H, s), 2.05 (3H, s);

MS m/z (M+H) 523.2;

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=3.33 min.

Example 16 Preparation of2-[2-(R,S)-1-(2,3-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(pyrid-4-yl)ethylacetamideand 2,3-dichloro-benzenesulfonyl chloride using Method G.

¹H NMR (DMSO-d₆) δ=10.25 (1H, s), 8.46 (2H, d, J=6.0 Hz), 7.91(2H, m),7.50 (2H, m), 7.22 (3H, m), 7.06 (1H, y), 6.87 (1H, d, J=9.0 Hz), 4.91(1H, q), 2.69 (2H, t), 2.25 (2H, m);

MS m/z (M+H) 520.4;

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=2.95 min.

Example 17 Preparationof2-[2-(R,S)-1-(2,3-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[(2-pyrid-4-yl)-eth-1-yl]-N-methylacetamide

2-[2-(R,S)-3-Oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]acetic acid wascoupled to commercially available 4-[2-(methylamino)ethyl]pyridine usingMethod I, followed by sulfonylation with 2,3-dichlorobenzene sulfonylchloride using Method G.

¹NMR (DMSO-d₆) δ=10.76 (1H, d, J=7.2 Hz), 8.46 (1H, d, J=5.7 Hz), 8.37(1H, d, J=6.0 Hz), 7.94 (2H, m), 7.53 (2H, m), 7.25 (2H, m), 7.05 (1H,t), 6.94 (2H, m), 4.98 (m, 1H), 4.88 (1H, dd), 2.69 (3H, s), 2.27 (1H,m);

MS m/z (M+H) 534.4;

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=3.16 min.

Example 18 Preparationof2-[2-(R,S)-1-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]-N-methylacetamide

2-[2-(R,S)-3-Oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]acetic acid wascoupled to commercially available 4-[2-(methylamino)ethyl]pyridine usingMethod I, followed by sulfonylation with4-methoxy-2,3,6-trimethyl-benzenesulfonyl chloride using Method G.

¹H NMR (DMSO-d₆) δ=10.72 (1H, m), 8.45 (1H, d, J=6.0 Hz), 8.37 (1H, d,J=6.0 Hz), 8.20 (1H, d, J=5.7 Hz), 7.24 (1H, m), 6.99 (4H, m), 6.85 (1H,s), 4.73 (1H, m), 4.56 (1H, m), 3.85 (3H d, J=3.0 Hz), 2.74 (3H, s),2.65 (3H, s), 2.39 (2H, d, J=4.8 Hz), 2.31 (2H, d, J=3.0 Hz), 2.04 (2H,d, J=9.0 Hz);

MS m/z (M+H) 537.2;

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=3.46 min.

Example 19 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(pyrrolidin-N-ylcarbonyl)-4-(N′-t-butoxycarbonyl)guanadino-n-but-1-yl]acetamide

Z-D-Arg-OH amino acid was protected using Method A′ followed by couplingwith pyrrolidine using Method I. Deprotection using Method B′ followedby coupling to2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzene-sulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid using Method S led to the desired material. The crude product waspurified via column chromatography (silica gel) eluted withCH₂Cl₂—MeOH-ammonia 9:1:0.1 and washed with a citric acid buffer toafford the title compound as a mixture of diastereomers.

¹H NMR (CDCl₃) δ=8.04 (1H, s), 7.63 (2H, m), 7.55 (1H, s), 7.49 (1H, s),7.21 (1H, d, J=7.8 Hz), 7.11 (1H, m), 2.90 (3H, s), 2.90 (3H, s), 2.23(2H, d, J=9.3 Hz), 2.07 (2H, d, J=8.4 Hz), 2.00 (1H, m), 1.86 (1H, m),1.51 (9H, s);

MS m/z (M+H) 719.2;

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=4.40 min.

Example 20 Preparation of 2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(pyrrolidin-N-ylcarbonyl)-5-(t-butoxy-carbonylamino)-pent-5-yl]acetamide

Z-D-Lys(Boc)-OH amino acid was coupled to pyrrolidine using Method Ifollowed by deprotection using Method B′, followed by coupling to2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]aceticacid using Method S. The crude material was purified via columnchromatography (silica gel) eluted with EtOAc—CH₃CN 95:5, separating thediastereomers to afford the title compound as a single diastereomer.

¹H NMR (DMSO-d₆) δ=10.44 (1H, s), 8.16 (1H, d, J=9.0 Hz), 7.45 (1H, s),7.32 (3H, m), 7.10 (1H, m), 6.81 (1H, d, J=8.7 Hz), 6.74 (1H, t), 4.87(1H, m), 4.45 (1H, m), 3.62 (1H, m), 3.43 (1H, m), 2.85 (2H, m), 2.73(1H, s), 2.29 (1H, m), 2.23 (3H, s), 1.92 (4H, m), 1.571H, m), 1.36 (9H,s);

MS m/z (M+H-Boc) 590.2;

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=6.01 min.

Example 21 Preparation of 2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-pyrrolidin-N-ylcarbonyl-5-(N′-t-butoxycarbonylamino)-pent-5-yl]acetamide

Z-D-Lys(Boc)-OH amino acid was coupled to pyrrolidine using Method I,followed by deprotection using Method B′, followed by coupling to2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid using Method S. The resulting material was purified via columnchromatography (silica gel) eluted with EtOAc—CH₃CN 95:5 separating thediastereomers to afford the title compound as a single diastereomer.

¹H NMR (DMSO-d₆) δ=10.45 (1H, s), 8.13 (1H, d, J=9.0 Hz), 7.40 (3H, m),7.26 (1H, t), 7.11 (1H, t), 6.77 (2H, m), 4.84 (1H, m), 4.44 (1H, m),3.55 (1H, m), 3.42 (1H, m), 3.22 (2H, m), 2.91 (2H, m), 2.73 (1H, s),2.24 (3H, s), 1.99 (2H, m), 1.86 (2H, m), 1.76 (1H, m), 1.38 (9H, s);

MS m/z (M+H-Boc) 590.2;

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=5.92 min.

Example 22 Preparation of 2-[2-(S orR)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(pyrrolidin-N-ylcarbonyl-4-guanidino-but-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(pyrrolidin-N-ylcarbonyl)-4-(N′-t-butoxy-carbonyl)-guanadino-n-but-1-yl]acetamidewas deprotected using Method O. The resulting pair of diastereomers waspurified by preparative HPLC (CH₃CN—H₂O-0.1% TFA) to afford the titlecompound as a single diastereomer.

¹H NMR (DMSO-d₆) δ=10.45 (1H, s), 8.26 (1H, d, J=8.7 Hz), 7.35 (5H, m),7.12 (2H, t), 6.80 (1H, d, J=9.0 Hz), 4.89 (1H, m), 4.55 (1H, m), 3.06(2H, m), 2.73 (1H, s), 2.30 (2H, m), 2.25 (3H, s), 1.97 (4H, m), 1.83(2H, m), 1.42 (3H, m);

MS m/z (M+H) 619.2;

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=3.45 min.

Example 23 Preparation of 2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(pyrrolidin-N-ylcarbonyl)-4-(guanadino)but-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(pyrrolidin-N-ylcarbonyl)-4-(N′-t-butoxy-carbonyl)-guanadino-n-but-1-yl]acetamidewas deprotected using Method O. The resulting pair of diastereomers waspurified by preparative HPLC (CH₃CN—H₂O-0.1% TFA) to afford the titlecompound as a single diastereomer.

¹H NMR (DMSO-d₆) δ=10.45 (1H, s), 8.24 (1H, d, J=8.4 Hz), 7.40 (4H, m),7.29 (1H, m), 7.11 (2H, m), 6.80 (1H, d, J=8.4 Hz), 4.87 (1H, t), 4.51(1H, m), 3.13 (2H, m), 2.73 (1H, s), 2.30 (2H, m), 2.23 (3H, s), 1.99(3H, s), 1.89 (2H, m), 1.77 (2H, m), 1.42 (3H, m);

MS m/z (M+H) 619.2;

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=3.68 min.

Example 24 Preparation of 2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(pyrrolidin-N-ylcarbonyl)-4-(t-butoxy-carbonylamino)-n-but-1-yl]acetamide

Z-D-Orn(Boc)-OH amino acid was coupled to pyrrolidine using Method Ifollowed by deprotection using Method B′, followed by coupling to2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid using Method S. The resulting material was purified via columnchromatography (silica gel) eluted with EtOAc—CH₃CN 95:5, separating thediastereomers to afford the title compound as a single diastereomer.

¹H NMR (DMSO-d₆) δ=10.45 (1H, s), 8.16 (1H, d, J=9.0 Hz), 7.32 (4H, m),7.11 (1H, t), 6.81 (1H, d, J=7.5 Hz), 6.73 (1H, s), 4.87 (1H, t), 4.47(1H, m), 3.60 (1H, m), 3.45 (1H, m), 2.87 (2H, m), 2.73 (1H, s), 2.30(2H, m), 2.23 (3H, s), 1.98 (4H, d, J=3.6 Hz), 1.94 (1H, s), 1.83 (2H,m), 1.55 (1H, m) 1.36 (9H, s);

MS m/z (M+H-Boc) 576.2;

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=5.78 min.

Example 25 Preparation of 2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(pyrrolidin-N-ylcarbonyl)-4-(N′-t-butoxy-carbonylamino)-n-but-1-yl]acetamide

Z-D-Orn(Boc)-OH amino acid was coupled to pyrrolidine using Method Ifollowed by deprotection using Method B′ followed by coupling to2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid using Method S. The resulting material was purified via columnchromatography (silica gel) eluted with EtOAc—CH₃CN 95:5 separating thediastereomers to afford the title compound as a single diastereomer.

¹H NMR (DMSO-d₆) δ=10.45 (1H, s), 8.15 (1H, d, J=8.1 Hz), 7.42 (3H, m),7.29 (1H, t), 7.10 (1H, t), 6.79 (2H, m), 4.84 (1H, t), 4.46 (1H, m),3.47 (2H, m), 2.91 (2H, m), 2.73 (1H, s), 2.29 (5H, m), 1.99 (4H, d,J=7.5 Hz), 1.88 (2H, m), 1.80 (2H, m), 1.57 (1H, m) 1.38 (9H, s);

MS m/z (M+H-Boc) 576.2;

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=5.76 min.

Example 26 Preparation of 2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(pyrrolidin-N-ylcarbonyl)-5-amino-n-pent-1-yl]acetamide

2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(pyrrolidin-N-ylcarbonyl)-5-(t-butoxy-carbonylamino)-pent-5-yl]acetamidewas deprotected using Method O to afford the title compound as a singlediastereomer.

¹H NMR (DMSO-d₆) δ=8.23 (1H, d, J=9.0 Hz), 7.77 (2H, s), 7.32 (4H, m),7.12 (1H, t), 6.82 (1H, d, J=6.0 Hz), 4.91 (1H, m), 4.51 (1H, m), 3.59(2H, m), 3.31 (2H, m), 2.74 (2H, s), 2.32 (2H, m), 2.27 (3H, s), 1.99(3H, s), 1.82 (3H, m), 1.50 (1H, m);

MS m/z (M+H) 591.3;

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=3.56 min.

Example 27 Preparation of 2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(pyrrolidin-N-ylcarbonyl)-5-amino-n-pent-1-yl]acetamide

2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzene-sulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-pyrrolidin-N-ylcarbonyl-5-(N′-t-butoxy-carbonylamino)-n-pent-5-yl]acetamidewas deprotected using Method O to afford the title compound as a singlediastereomer.

¹H NMR (DMSO-d₆) δ=8.20 (1H, d, J=8.4 Hz), 7.83 (2H, s), 7.39 (3H, m),7.30 (1H, t), 7.15 (1H, t), 6.81 (1H, d, J=7.8 Hz), 4.87 (1H, m), 4.51(1H, m), 3.27 (2H, m), 2.80 2H, m), 2.30 (2H, m), 2.23 (3H, s), 1.91(4H, m), 1.79 (2H, m), 1.60 (3H, m) 1.39 (2H, m);

MS m/z (M+H) 591.3;

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=3.32 min.

Example 28 Preparation of 2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(pyrrolidin-N-ylcarbonyl)-4-amino-n-butyl]acetamide

2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzene-sulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(pyrrolidin-N-ylcarbonyl)-4-(t-butoxy-carbonylamino)-n-butyl]acetamidewas deprotected using Method O to afford the title compound as a singlediastereomer.

¹H NMR (DMSO-d₆) δ=10.47 (1H, s), 8.27 (1H, d, J=8.4 Hz), 7.69 (2H, s),7.33 (4H, m), 7.15 (1H, t), 6.81 (1H, d, J=9.6 Hz), 4.91 (1H, m), 4.56(1H, m), 3.47 (2H, m), 2.75 (2H, m), 2.28 (2H, m), 2.22 (3H, s), 1.88(4H, m), 1.50 (1H, m), 1.18 (3H, m);

MS m/z (M+H) 577.2;

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=3.25 min.

Example 29 Preparation of 2-[2-(S orR)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(pyrrolidin-N-ylcarbonyl)-4-amino-n-butyl]acetamide

2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzene-sulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(pyrrolidin-N-ylcarbonyl)-4-(N′-t-butoxy-carbonylamino)-n-butyl]acetamidewas deprotected using Method O to afford the title compound as a singlediastereomer.

¹H NMR (DMSO-d₆) δ=10.46 (1H, s), 8.29 1H, d, J=8.4 Hz), 7.72 (2H, s),7.42 (3H, m), 7.30 (1H, t), 7.12 (1H, t), 6.80 (1H, d, J=7.8 Hz), 4.91(1H, m), 4.50 (1H, m), 3.49 (2H, m), 2.79 (2H, m), 2.30 (2H, m), 2.22(3H, s), 1.88 (4H, m), 1.53 (4H, m);

MS m/z (M+H) 577.2;

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=3.36 min.

Example 30 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-4-methyl-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(N-methyl-1,2,5,6-tetrahydropyrid-4-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-4-methyl-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamideby Method J.

¹H NMR (d₆-DMSO HCl salt) δ=8.02-7.99 (m, 1H), 7.47-7.41 (m, 4H),7.30-7.25 (m, 1H), 7.16 (d, J=8.1 Hz, 1H), 5.43-5.38 (m, 1H), 5.05-4.99(m, 1H), 3.70-3.47 (m, 3H), 3.22-2.97 (m, 3H), 2.77-2.74 (m, 6H),2.60-2.47 (m, 1H), 2.33-2.16 (m, 6H), 2.13-2.07 (m, 2H), 1.98-1.97 (s,3H);

MS (ES): m/e 546 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=3.85 min.

Example 31 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-methylenecarbonyl-(N-morpholino)

The title compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-di-methylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and morpholine using Method I.

¹H NMR (d₆-DMSO) δ=10.60 (s), 7.54-7.46 (m, 3H), 7.32 (t, J=7.8 Hz, 1H),7.18-7.14 (m, 1H), 6.88 (d, J=7.8 Hz, 1H), 4.93 (t, J=6.0 Hz, 1H),3.57-3.50 (m, 4H), 3.47-3.40 (m, 2H), 3.35 (d, J=6.6 Hz, 2H), 3.29-3.24(m, 2H), 2.28 (s, 3H), 2.07 (s, 3H););

MS: m/z (EI+) 479 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=4.98 min.

Example 32 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{[2-N-(t-butoxycarbonylmethyl)pyridin-4-yl]eth-1-yl}acetamide

This title compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamideand t-butyl bromoacetate using the procedure described for the synthesisof2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-4-t-butoxy-carbonylmethyl-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(t-butoxy-carbonylmethyl)piperidin-4-yl]eth-1-yl}acetamide.

¹H NMR (d₆-DMSO) δ=10.47 (s, 1H), 8.90 (d, J=7.8 Hz, 2H), 8.13 (bs, 1H),8.05 (d, J=7.8 Hz, 2H), 7.41-7.25 (m, 4H), 7.09 (t, J=7.8 Hz, 1H), 6.81(d, J=7.8 Hz, 1H), 5.49 (s, 2H), 4.85-4.81 (m, 1H), 3.42 (bs, 2H), 3.02(bs, 2H), 2.27-2.06 (m, 5H), 1.96 (s, 3H), 1.45 (s, 9H);

¹³C NMR (d₆-DMSO) δ=167.92, 166.77, 166.09, 161.72, 145.94, 139.19,137.31, 134.65, 134.24, 133.98, 133.33, 132.63, 129.23, 128.84, 128.47,123.56, 121.60, 116.50, 84.28, 60.53, 56.40, 38.53, 36.72, 35.34, 28.12,19.39, 19.35;

MS: m/z (EI+) 628 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=4.33 min.

Example 33 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylsulfonyl)-3-oxo-4-methyl-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]-N-methylacetamide

This compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-dimethylsulfonyl)-3-oxo-4-methyl-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and 4-methyl aminoethylpyridine using Method I.

¹H NMR (d₆-DMSO) δ=8.83 (d, J=6.6 Hz, 1.5H), 8.72 (d, J=6.6 Hz, 0.5H),7.93 (d, J=6.6 Hz, 1.5H), 7.58 (d, J=6.6 Hz, 0.5H), 7.51-7.39 (m, 4H),7.29-7.16 (m, 2H), 5.11-5.01 (m, 1H), 3.71-3.80 (m, 1H), 3.53-3.62 (m,1H), 3.06 (t, J=6.6 Hz, 2H), 2.82 2.74 (m, 6H), 2.48-2.30 (m, 2H), 2.27(s, 3H), 2.00 (s, 0.5H), 1.96 (s, 1.5H);;

MS: m/z (EI+) 542 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=3.92 min.

Example 34 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-4-benzyl-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamide

This compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-dimethyl-benzenesulfonyl)-3-oxo-4-benzyl-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and 4-aminoethyl pyridine using Method I.

¹H NMR (d₆-DMSO) δ=8.74 (d, J=5.4 Hz, 2H), 8.13 (t, J=4.5 Hz, 1H), 7.84(d, J=5.4 Hz, 2H), 7.59-7.42 (m, 3H), 7.36-7.16 (m, 6H), 7.06 (d, J=7.2Hz, 1H), 6.94 (d, J=7.2 Hz, 1H), 5.12-5.07 (m, 1H), 4.84 (d, J=16.8 Hz,1H), 4.48 (d, J=16.8 Hz, 1H), 3.35-3.45 (m, 2H), 2.97-2.87 (m, 2H),2.41-2.26 (m, SH), 2.09 (s, 3H).

Example 35 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(pyrid-2-yl)piperidin-4-yl]eth-1-yl}acetamide

This compound was synthesized from2-[(R,S)-1-(4-chloro-2,5-dimethyl-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-aceticacid and [N-(pyrid-2-yl)piperidin-4-yl]eth-1-ylamine using Method I.

¹H NMR (d₆-DMSO, parent) δ=10.51 (s, 1H), 8.11 (d, J=6.6 Hz, 1H), 7.92(bs, 1H), 7.55-7.44 (m, 4H), 7.33 (t, J=7.8 Hz, 1H), 7.15 (t, J=7.8 Hz,1H), 6.85 (t, J=7.8 Hz, 2H), 6.60 (dd, J=5.7, 7.8 Hz, 1H), 4.91 (dd,J=4.5, 9.3 Hz, 1H), 4.33-4.29 (m, 2H), 3.21-3.13 (m, 1H), 3.04-2.97 (m,1H), 2.81 (t, J=12.0 Hz, 2H), 2.33-2.13 (m, 5H), 2.04 (s, 3H), 1.81-1.05(m, 7H);

¹³C-NMR (d₆-DMSO) δ=166.70, 147.82, 138.75, 137.73, 137.01, 134.26,134.02, 132.95, 132.37, 128.83, 128.48, 123.15, 121.38, 112.48, 107.29,56.32, 45.15, 36.24, 36.10, 33.00, 31.54, 31.43, 19.31, 19.21;

MS: m/z (EI+) 597 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=3.92 min.

Example 36 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(4-fluorophenethyl)acetamide

This compound was synthesized from2-[(R,S)-1-(4-chloro-2,5-dimethyl-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and 4-fluorophenyl ethylamine using Method I.

¹H NMR (d₆-DMSO) δ=10.46 (s, 1H), 7.96 (t, J=5.4 Hz, 1H), 7.47-7.06 (m,9H), 6.81 (d, J=8.1 Hz, 1H), 4.86 (dd, J=5.1, 9.0 Hz, 1H), 3.26-3.10 (m,2H), 2.63 (t, J=7.2 Hz, 2H), 2.25-2.10 (m, 5H), 2.01 (s, 3H);

MS: m/z (EI+) 531 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=6.17 min.

Example 37 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-acetamidophenethyl)acetamide

This compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-aminophenyl)eth-1-yl]acetamideand acetic anhydride using Method Q′.

¹H NMR (d₆-DMSO) δ=10.52 (s, 1H), 9.90 (s, 1H), 8.00 (bs, 1H), 7.54-7.41(m, 5H), 7.32 (t, J=7.8 Hz, 1H), 7.15-7.11 (m, 3H), 6.86 (d, J=7.8 Hz,1H), 4.91 (dd, J=4.8, 9.0 Hz, 1H), 3.33-3.11 (m, 2H), 2.63 (t, J=6.9 Hz,2H), 2.19-2.14 (m, 5H), 2.05 (s, 6H);

MS: m/z (EI+) 570 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=3.35 min.

Example 38 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[4-(N′,N′-dimethylamino)-phenethyl]}acetamide

This compound was synthesized from2-[(R,S)-1-(4-chloro-2,5-dimethyl-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and 2-[4-(N,N-dimethylamino)phen-1-yl]eth-1-ylamine using Method I.

¹H NMR (d₆-DMSO) δ=10.52 (s, 1H), 7.97 (t, J=5.1 Hz, 1H), 7.53-7.41 (m,3H), 7.32 (t, J=7.8 Hz, 1H), 7.13 (t, J=7.8 Hz, 1H), 7.04 (d, J=7.8 Hz,2H), 6.87 (d, J=8.1 Hz, 1H), 6.71 (d, J=7.8 Hz, 2H), 4.92 (dd, J=5.1,8.7 Hz, 1H), 3.23-3.09 (m, 2H), 2.88 (s, 6H), 2.56-2.53 (m, 2H),2.31-2.15 (m, 5H), 2.07 (s, 3H);

MS: m/z (EI+) 556 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=2.58 min.

Example 39 Preparation of2-[2-(S)-1-(2,3-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-aminophen-1-yl)ethy-1-yl]acetamide

This compound was synthesized from2-[2-(R,S)-1-(2,3-dichlorobenzene-sulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and 4-amino phenylethyl amine using Method I.

¹H NMR (d₆-DMSO) δ=10.67 (s, 1H), 7.97-7.87 (m, 3H), 7.51 (t, J=7.8 Hz,2H), 7.22 (t, J=7.2 Hz, 1H), 7.05 (t, J=7.2 Hz, 1H), 6.89-6.76 (m, 3H),6.48 (d, 2H), 4.97-4.87 (m, 1H), 4.82 (bs, 2H), 3.28-2.98 (m, 4H),2.25-2.16 (m, 2H);

MS: m/z (EI+) 534 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=2.20 min.

Example 40 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-6,7-difluoroquinoxalin-2-yl]-N-[(2-pyrid-4-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzene-sulfonyl)-3-oxo-1,2,3,4-tetrahydro-6,7-difluoroquinoxalin-2-yl]aceticacid and 4-(2-aminoethyl)pyridine using Method I.

¹H NMR (d₆-DMSO) δ=10.60 (s, 1H), 8.76 (d, J=6.6 Hz, 2H), 8.04 (t, J=3.6Hz, 1H), 7.79 (d, J=6.6 Hz, 2H), 7.47 (d, J=4.8 Hz, 2H), 7.35 (dd,J=7.8, 11.1 Hz, 1H),6.81 (dd, J=7.8, 11.1 Hz, 1H),4.92(dd, J=5,1,9,6 Hz,1H), 3.47-3.31 (m, 2H), 2.95-2.91 (m, 2H), 2.25-2.09 (m, 8H);

MS: m/z (EI+) 550 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=2.69 min.

Example 41 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-6,7-difluoroquinoxalin-2-yl]-N-[2-(4-aminophenyl)eth-1-yl]acetamide

This compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-6,7-difluoroquinoxalin-2-yl]aceticacid and 4-amino-phenethylamine using Method I.

¹H NMR (d₆-DMSO) δ=10.61 (s, 1H), 7.99 (t, J=5.1 Hz, 1H), 7.50 (d, J=6.0Hz, 2H), 7.39 (dd, J=8.1, 11.1 Hz, 1H), 7.25 (d, J=8.1 Hz, 2H), 7.14 (d,J=8.1 Hz, 2H), 6.84 (dd, J=8.1, 11.1 Hz, 1H), 4.79 (dd, J=4.5, 8.7 Hz,1H), 3.25-3.09 (m, 2H), 2.65 (t, J=7.2 Hz, 2H), 2.26-2.06 (m, 8H);

MS: m/z (EI+) 563 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=2.77 min.

Example 42 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[-(N′,N′-dimethylaminocarbonyl)piperidin-4-yl]eth-1-yl}acetamide

This compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(piperidin-4-yl)eth-1-yl]acetamideand dimethylcarbamyl chloride using Method R′.

¹H NMR (d₆-DMSO) δ=10.50 (s, 1H), 7.90 (t, J=5.1 Hz, 1H), 7.49-7.43 (m,3H), 7.33 (dt, J=1.2, 7.5 Hz, 1H), 7.16 (dt, J=1.2, 7.5 Hz, 1H), 6.87(dd, J=1.2, 7.5 Hz, 1H), 4.91 (dd, J=4.8, 9.9 Hz, 1H), 3.58-3.53 (m,2H), 3.19-3.10 (m, 1H), 3.05-2.94 (m, 1H), 2.74-2.65 (m, 8H), 2.32-2.12(m, 5H), 2.05 (s, 3H), 1.75-1.03 (m, 7H);

MS: m/z (EI+) 591 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=3.75 min.

Example 43 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(N′,N′-dimethylaminocarbonyl)aminophen-1-yl]}acetamide

This compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-4-t-butoxy-carbonylmethyl-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(t-butoxycarbonylmethyl)piperidin-4-yl]eth-1-yl}acetamideand dimethylcarbamyl chloride using Method R′.

¹H NMR (d₆-DMSO) δ=10.52 (s, 1H), 8.23 (s, 1H), 8.01 (t, J=5.7 Hz, 1H),7.53-7.40 (m, 5H), 7.32 (dt, J=1.2, 7.5 Hz, 1H), 7.16-7.10 (m, 3H), 6.87(dd, J=1.2, 7.5 Hz, 1H), 4.91 (dd, J=4.8, 9.9 Hz, 1H), 3.28-3.09 (m,2H), 2.95 (s, 6H), 2.61 (t, J=7.5 Hz, 2H), 2.28-2.09 (m, 5H), 2.07 (s,3H);

MS: m/z (EI+) 599 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=3.78 min.

Example 44 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(pyridin-2-yl)piperidin-4-yl]eth-1-yl}acetamide

The title compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and 2-[N-(pyrimidin-2-yl)piperidin-4-yl]ethylamine using Method I.

¹H NMR (d₆-DMSO) δ=10.46 (s, 1H), 8.30 (d, J=5.0 Hz, 2H), 7.86 (t, J=5.7Hz, 1H), 7.45-7.39 (m, 3H), 7.28 (t, J=7.5 Hz, 1H), 7.11 (t, J=7.5 Hz,1H), 6.81 (d, J=7.5 Hz, 1H), 6.54 (t, J=5.0 Hz, 1H), 4.86 (dd, J=4.8,9.3 Hz, 1H), 4.65-4.62 (m, 2H), 3.16-3.09 (m, 1H), 2.98-2.91 (m, 1H),2.87-2.79 (m, 2H), 2.28-2.07 (m, 5H), 1.99 (s, 3H), 1.77-0.95 (m, 7H);

MS: m/z (EI+) 598 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=3.21 min.

Example 45 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(thiazol-2-yl)piperidin-4-yl]eth-1-yl}acetamide

The title compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-di-methylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and 2-[N-(thiazol-2-yl)piperidin-4-yl]ethylamine using Method I.

¹H NMR (CDCl₃) δ=8.10 (s, 1H), 7.64 (dd, J=1.2, 8.1 Hz, 1H), 7.52 (s,1H), 7.29-7.24 (m, 1H), 7.18-7.12 (m, 3H), 6.74 (dd, J=1.2, 8.1 Hz, 1H),6.52 (d, J=3.3 Hz, 1H), 6.15 (t, J=5.4 Hz, 1H), 5.05 (dd, J=3.6, 9.9 Hz,1H), 4.02-3.96 (m, 2H), 3.37-3.27 (m, 2H), 3.11-3.00 (m, 2H), 2.55 (dd,J=4.2, 15.9 Hz, 1H), 2.36 (dd, J=10.5, 15.9 Hz, 1H), 2.25 (s, 3H), 1.97(s, 3H), 1.88-1.36 (m, 7H);

¹³C NMR (CDCl₃) δ=167.87, 162.73, 162.16, 135.36, 134.92, 132.17,130.28, 128.87, 128.51, 127.73, 127.32, 124.28, 123.94, 119.75, 117.00,111.34, 102.26, 51.44, 44.37, 44.33, 32.44, 32.22, 31.17, 28.30, 26.55,26.46, 15.04, 14.57;

MS: m/z (EI+) 603 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=3.02 min.

Example 46 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[4-N′,N′-dimethylaminocarbonyloxy)pheneth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-di-methylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-aceticacid and 2-[4-(N,N-dimethylcarbamate)]ethylamine using Method I.

¹H NMR (d₆-DMSO) δ=10.52 (s, 1H), 8.05 (t, J=5.7 Hz, 1H), 7.53 (s, 1H),7.48 (s, 1H), 7.42 (d, J=8.1 Hz, 1H), 7.32 (t, J=8.1 Hz, 1H), 7.23 (d,J=8.4 Hz, 2H), 7.14 (t, J=8.1 Hz, 1H), 7.06 (d, J=8.4 Hz, 2H), 6.87 (d,J=8.1 Hz, 1H), 4.93 (dd, J=5.1, 9.0 Hz, 1H), 3.32-3.17 (m, 2H), 3.07 (s,3H), 2.94 (s, 3H), 2.69 (t, J=7.2 Hz, 2H), 2.30-2.16 (m, 5H), 2.07 (s,3H);

MS: m/z (EI+) 600 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=4.33 min.

Example 47 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(methylcarbonylmethylene)piperidin-4-yl]eth-1-yl}acetamide

This compound was synthesized by alkylation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(piperidin-4-yl)eth-1-yl]acetamidewith chloroacetone using DIEA in EtOH at room temperature.

¹H NMR (d₆-DMSO) δ=10.53 (s, 1H), 7.98 (bs, 1H), 7.48-7.43 (m, 3H), 7.34(t, J=8.1 Hz, 1H), 7.17 (t, J=8.1 Hz, 1H), 6.88 (d, J=8.1 Hz, 1H), 4.92(dd, J=4.5, 9.3 Hz, 1H), 4.35 (s, 2H), 3.45-3.41 (m, 2H), 3.23-3.15 (m,2H), 3.05-2.96 (m, 2H), 2.61-2.47 (m, 1H), 2.34-2.11 (m, 7H), 2.03 (s,3H), 1.95-1.29 (m, 7H);

MS: m/z (EI+) 576 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=2.79 min.

Example 48 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(pyrid-2-yl)piperdin-4-yl]eth-1-yl}acetamide

The title compound was synthesized using the same method described forthe synthesis of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzene-sulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(pyrid-2-yl)piperidin-4-yl]eth-1-yl}acetamidestarting with2-[2-(R)-1-(4-chloro-2,5-dimethyl-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid.

¹H NMR (d₆-DMSO, HCl salt) δ=10.51 (s, 1H), 8.03-7.96 (m, 3H), 7.55-7.41(m, 4H), 7.34 (t, J=7.5 Hz, 1H), 7.18 (t, J=7.5 Hz, 1H), 6.94-6.86 (m,2H), 4.91 (dd, J=5.1, 9.9 Hz, 1H), 4.31-4.27 (m, 2H), 3.39-3.17 (m, 3H),3.05-3.01 (m, 1H), 2.65-2.46 (m, 1H), 2.34-2.12 (m, 4H), 2.03 (s, 3H),1.96-1.73 (m, 3H), 1.39-1.09 (m, 4H);

MS: m/z (EI+) 597 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=3.03 min.

Example 49 Preparation of2-[2-(R,S)-1-(2,3-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(pyrid-2-yl)piperidin-4-yl]eth-1-yl}acetamide

The title compound was synthesized using the procedure described for2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]-N-{2-[N-(pyrid-2-yl)piperidin-4-yl]eth-1-yl}acetamideusing2-[2-(R,S)-1-(2,3-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and N-[2-N-(pyrid-2-yl)piperidin-4-yl]eth-1-yl amine as a startingmaterial

¹H NMR (d₆-DMSO) δ=10.71 (s, 1H), 8.12 (d, J=5.1 Hz, 1H), 7.99 (d, J=8.1Hz, 1H), 7.93-7.89 (m, 2H), 7.57-7.49 (m, 3H), 7.26 (t, J=7.8 Hz, 1H),7.10 (t, J=7.8 Hz, 1H), 6.92 (d, J=7.5 Hz, 1H), 6.84 (d, J=8.1 Hz, 1H),6.60 (t, J=7.8 Hz, 1H), 4.97 (dd, J=5.1, 9.3 Hz, 1H), 4.33-4.29 (m, 2H),3.18-3.09 (m, 1H), 3.07-2.96 (m, 1H), 2.79 (t, J=12.6 Hz, 2H), 2.37-2.32(m, 2H), 1.81-1.05 (m, 7H);

MS: m/z (EI+) 603 (M⁺,+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=2.71 min.

Example 50 Preparation of2-[2-(R,S)-1-(2,3-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-methyl-N-{2-[N-(pyrid-2-yl)piperidin-4-yl]eth-1-yl}acetamide

The title compound was synthesized using Method I fromN-methyl-N-[(pyrid-2-ylpiperidin-4-yl)eth-1-yl]amine and2-[2-(R,S)-1-(2,3-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid.

MS: m/z (EI+) 617 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=2.86 min.

Example 51 Preparation of2-[2-(R,S)-1-(2,3-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[1-(N-(methylimidizol-4-yl)eth-1-yl]}acetamide

The title compound was synthesized from2-[2-(R,S)-1-(2,3-dichloro-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and 1-methyl-histamine using Method I.

¹H NMR (¹H) δ=7.92 (dd, J=1.8, 7.5 Hz, 1H), 7.75 (dd, J=1.8, 7.5 Hz,1H), 7.57 (dd, J=1.8, 7.5 Hz, 1H), 7.49 (s, 1H), 7.36 (t, J=7.8 Hz, 1H),7.19 (dt, J=1.8, 7.5 Hz, 1H), 7.05 (dt, J=1.8, 7.5 Hz, 1H), 6.90-6.84(m, 2H), 5.23 (dd, J=4.8, 9.9 Hz, 1H3.69 (s, 3H), 3.49-3.3.39 (m, 1H),3.36-3.26 (m, 1H), 2.70 (t, J=7.2 Hz, 2H), 2.46 (dd, J=4.8, 14.1 Hz,1H), 2.34 (dd, J=9.9, 14.1 Hz, 1H);

¹³C NMR (CD₃OD) δ=163.95, 163.12, 134.21, 132.57, 130.73, 130.59,121.52, 126.76, 125.38, 123.00, 122.81, 121.69, 118.54, 116.99, 112.81,111.28, 52.06, 34.28, 32.03, 27.43, 22.55;

MS: m/z (EI+) 523 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=2.36 min.

Example 52 Preparation of2-[2-(R,S)-1-(2,3-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(N′,N′-dimethylamino)eth-1-yl]acetamide

This compound was synthesized from2-[2-(R,S)-1-(2,3-dichloro-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and N′,N′-dimethylethylenediamine using Method I.

¹H NMR (d₆-DMSO, parent) δ=10.78 (s, 1H), 8.30 (t, J=5.1 Hz, 1H), 8.01(dd, J=1.8, 8.4 Hz, 1H), 7.91(dd, J=1.8, 8.4 Hz, 1H), 7.59-7.53 (m, 2H),7.27 (dt, J=1.8, 7.8 Hz, 1H), 7.10 (t, J=7.8 Hz, 1H), 6.93 (d, J=7.8 Hz,1H), 5.02 (dd, J=4.2, 8.7 Hz, 1H), 3.43-3.36 (m, 2H), 3.14-3.07 (m, 2H),2.84 (s, 3H), 2.83 (s, 3H), 2.60-2.26 (m, 2H);

MS: m/z (EI+) 486 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=2.38 min.

Example 53 Preparation of2-[2-(R,S)-1-(2,3-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(imidizol-4-yl)eth-1-yl]acetamide

This compound was synthesized from2-[2-(R,S)-1-(2,3-dichloro-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and histamine using Method I.

MS: m/z (EI+) 509 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column, low gradient): R_(t)=13.50 min.

Example 54 Preparation of2-[2-(R,S)-1-(5-chloro-1,3-dimethylpirazol-4-ylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-(3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]-N-(pyrid-4-yl)ethylacetamideand 2-chloro 3-N-methyl 5-methylpyrazole sulfonyl chloride using MethodG.

¹H NMR (DMSO-d₆) δ=8.47 (2H, d, J=6.0 Hz), 8.00 (1H, t), 7.26 (4H, m),7.09 (1H, t), 6.84 (1H, d, J=9.0 Hz), 4.92 (1H, m), 4.10 (1H, q), 3.70(3H, s), 3.23 (2H, m), 2.69 (2H, m), 2.18 (m, 2H), 1.81 (3H, s);

¹³C NMR (DMSO-d₆) δ=167.26, 166.91, 149.75, 148.69, 148.04, 133.69,130.01, 129.16, 128.95, 124.56, 123.12, 121.28, 116.03, 112.87, 55.97,36.94, 36.49, 34.32, 13.01;

MS m/z (M+H) 504;

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=6.69.

Example 55 Preparation of 2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(pyrrolidin-N-ylcarbonyl)-2-(4-iodophenyl)-eth-1-yl]acetamide

Boc-D-p-iodo phenylalanine was coupled with pyrrolidine using Method Sto affordN-Boc-{1-(R)-[pyrrolidin-N-ylcarbonyl]-2-(4-iodophenyl)}eth-1-ylamine(compound 1061) which was deprotected using Method O and coupled to2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]aceticacid using Method S. The resulting material was purified via columnchromatography (silica gel) eluted with EtOAc-Hexanes 1:4 separating thediastereomers to afford the title compound as a single diastereomer.

¹H NMR (CD₃OD) δ=7.59 (3H, m), 7.49 (1H, s), 7.23 (3H, m), 7.01 (2H, d,J=8.1 Hz), 6.82 (1H, d, J=9.3 Hz), 5.07 (1H, m), 3.72 (1H, m), 3.46 (1H,m), 3.06 (1H, m), 2.95 (1H, m), 2.83 (1H, m), 2.38 (2H, m), 2.26 (3H,s), 1.99 (3H, s), 1.75 (2H, m);

MS m/z (M+H) 736.

Example 56 Preparation of 2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(pyrrolidin-N-ylcarbonyl)-2-(4-iodophenyl)eth-1-yl]acetamide

Boc-D-p-iodo phenylalanine was coupled with pyrrolidine using Method Sto affordN-Boc-{1-(R)-[pyrrolidin-N-ylcarbonyl]-2-(4-iodophenyl)}eth-1-yl-amine(compound 1061) which was deprotected using Method O and coupled to2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]aceticacid using Method S. The resulting material was purified via columnchromatography (silica gel) eluted with EtOAc-Hexanes. 1:4 separatingthe diastereomers to afford the title compound as a single diastereomer.

¹H NMR (CD₃OD) δ=7.56 (2H, d, J=13.2 Hz), 7.51 (1H, s), 7.32 (3H, m),7.13 (3H, m), 6.81 (1H, d, J=9.0 Hz), 5.08 (1H, m), 3.68 (1H, m), 3.46(1H, m), 3.01 (1H, m), 2.96 (1H, m), 2.89 (1H, m), 2.40 (2H, m), 2.28(3H, s), 2.17 (3H, s), 1.91 (2H, m);

MS m/z (M+H) 735.

Example 57 Preparation of 2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[4-(N-t-butoxycarbonylpyrrol-2-yl)phenyl]eth-1-yl}acetamide

The title compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-dimethyl-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and 2-Boc-pyrrole boronic acid using Method C′ affording the titlecompound as a single diastereomer.

¹H NMR (CDCl₃) δ=8.02 (1H, s), 7.68 (1H, d, J=8.4 Hz), 7.54 (1H, s),7.35 (3H, m), 7.20 (2H, m), 7.04 (2H, m), 6.74 (1H, d, J=7.8 Hz), 6.22(1H, m), 6.15 (1H, m), 5.19 (1H, m), 5.00 (1H, m), 3.53 (1H, m), 3.00(1H, m), 2.42 (2H, m), 2.26 (3H, s), 2.07 (3H, s), 1.42 (9H, s);

MS m/z (M+H) 775;

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=4.67 min.

Example 58 Preparation of 2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(pyrrolidin-N-ylcarbonyl)-2-(4-biphenyl)eth-1-yl]acetamide

D-Biphenylalanine was protected with di-tert butyl dicarbonate using theprotection aspects of Method A′ followed by coupling with pyrrolidineusing Method I, followed by deprotection using Method O, followed bycoupling with2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]aceticacid using Method I. The residue was purified via column chromatography(silica gel) eluted with EtOAc-Hexanes, 1:4 and prep plate (silica gel),eluted with EtOAc-Hex, 1:9 separating the diastereomers to afford thetitle compound as a single diastereomer.

¹H NMR (DMSO-d₆) δ=10.47 (1H, s), 8.41 (1H, d, J=9.0 Hz), 7.62 (2H, d,J=9.0 Hz), 7.54 (2H, d, J=9.0 Hz), 7.34 (10H, m), 7.12 (1H, t), 6.82(1H, d, J=9.0 Hz), 4.83 (1H, m), 4.69 (1H, m), 3.50 (1H, m), 2.90 (1H,m), 2.74 (1H, m), 2.25 (3H, s), 1.99 (3H, s), 1.79 (3H, m);

MS m/z (M+H) 686;

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=7.03 min

Example 59 Preparation of 2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(pyrrolidin-N-ylcarbonyl)-2-(4-biphenyl)ethy-1-yl]acetamide

D-Biphenylalanine was protected using the protection aspects of MethodA′ followed by coupling with pyrrolidine using Method I, followed bydeprotection using Method O, followed by coupling with2-[2-(R,S)-1-(4-chloro-2,5-di-methylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid using Method I. The residue was purified via column chromatography(silica gel) eluted with EtOAc-Hexanes, 1:4 and prep plate (silica gel)eluted with EtOAc-Hex, 1:9 separating the diastereomers to afford thetitle compound as a single diastereomer.

¹H NMR (DMSO-d₆) δ=10.47 (1H, s), 8.39 (1H, d, J=6.0 Hz), 7.61 (4H, m),7.36 (10H, m), 7.04 (1H, t), 6.81 (1H, d, J=9.0 Hz), 4.8 (1H, t), 4.66(1H, dd), 3.49 (1H, m), 2.91 (1H, m), 2.76 (1H, m), 2.23 (3H, s), 1.99(3H, s), 1.76 (3H, m);

MS m/z (M+H) 686;

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=6.99 min.

Example 60 Preparation of 2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[4-(pyrid-2-yl)phenyl]eth-1-yl}acetamide

The title compound was synthesized from compound 1061 and 2-pyridylusing Method D′, followed by deprotection using Method P, followed bycoupling with2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzene-sulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]aceticacid using Method I. The resulting-material was purified via columnchromatography (silica gel) eluted with EtOAc—CH₃CN-95:5. Triturationwith MeOH afforded the separation of the diastereomers to afford thetitle compound as a single diastereomer.

¹H NMR (DMSO-d₆) δ=10.47 (1H, s), 8.64 (1H, d, J=6.0 Hz), 8.41 (1H, d,J=9.0 Hz), 7.89 (4H, m), 7.33 (6H, m), 7.12 (1H, t), 6.82 (1H, d, J=9.0Hz), 4.83 (1H, m), 4.72 (1H, m), 3.51 (1H, m), 2.94 (2H, m), 2.70 (2H,m), 2.22 (3H, s), 1.99 (3H, s), 1.81 (3H, m);

MS m/z (M+H) 687;

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=4.13 min.

Example 61 Preparation of 2-[2-(S orR)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[4-(pyrid-2-yl)phenyl]eth-1-yl}acetamide

The title compound was synthesized from compound 1061 and 2-pyridylstannane using Method D′, followed by deprotection using Method P,followed by coupling with2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzene-sulfonyl)-3-oxo-1,2,3,4-tetra-hydroquinoxalin-2-yl]aceticacid using Method I. The resulting material was purified via columnchromatography (silica gel), eluted with EtOAc—CH₃CN-95:5. Triturationwith MeOH afforded the separation of the diastereomers to afford thetitle compound as a single diastereomer.

¹H NMR (DMSO-d₆) δ=10.48 (1H, s), 8.67 (1H, d, J=3.0 Hz), 8.39 (1H, d,J=6.0 Hz), 7.91 (4H, m), 7.31 (6H, m), 7.03 (1H, t), 6.82 (1H, d, J=6.0Hz), 4.83 (1H, m), 4.64 (1H, m), 3.49 (1H, m), 2.85 (2H, m), 2.76 (2H,m), 2.22 (3H, s), 1.99 (3H, s), 1.75 (3H, m);

MS m/z (M+H) 687;

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=3.99 min.

Example 62 Preparation of 2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R)-(pyrrolidin-N-ylcarbonyl)-2-[4-(pyrimidin-2-yl)phenyl]eth-1-yl}acetamide

1-[(R)-1-pyrrolidin-1-ylcarbonyl-1-(t-butoxycarbonylamino)-1-(4-(2-pyrimidinyl)phenyl]ethanewas synthesized from compound 1061 and bromopyrimidine using Method E′followed by deprotection using Method P followed by coupling with2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid using Method I. The resulting material was purified via columnchromatography (silica gel) (EtOAc—CH₃CN-95:5) and prep plate (silicagel) (EtOAc—CH₃CN-9:1) separating the diastereomers to afford the titlecompound as a single diastereomer.

¹H NMR (300 MHz, (DMSO-d₆) δ=10.47 (1H, s), 8.88 (1H, d, J=6.0 Hz), 8.43(1H, d, J=6.0 Hz), 8.26 (1H, d, J=9.0 Hz), 7.34 (6H, m), 7.12 (1H, t),6.82 (1H, d, J=9.0 Hz), 4.82 (1H, m), 4.73 (1H, m), 3.51 (1H, m), 2.99(2H, m), 2.72 (2H, m), 2.22 (3H, s), 1.99 (3H, s);

MS m/z (M+H) 688;

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=3.84 min.

Example 63 Preparation of 2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[4-(pyrimidin-2-yl)phenyl]eth-1-yl}acetamide

1-[(R)-1-pyrrolidin-1-ylcarbonyl-1-(t-butoxycarbonylamino)-1-(4-(2-pyrimidinyl)phenyl]ethanewas synthesized from compound 1061 and bromopyrimidine using Method E′,followed by deprotection using Method P followed by coupling with2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzene-sulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid using Method I. The resulting material was purified via columnchromatography (silica gel), eluted with EtOAc—CH₃CN-95:5 and prep plate(silica gel) eluted with EtOAc—CH₃CN-9:1 separating the diastereomers toafford the title compound as a single diastereomer.

¹H NMR (DMSO-d₆) δ=10.48 (1H, s), 8.91 (1H, d, J=3.0 Hz), 8.31 (1H, d,J=6.0 Hz), 7.35 (6H, m), 7.06 (1H, t), 6.82 (1H, d, J=9.0 Hz), 4.83 (1H,m), 4.66 (1H, m), 3.47 (1H, m), 2.91 (2H, m), 2.64 (2H, m), 2.22 (3H,s), 1.98 (3H, s);

MS m/z (M+H) 688;

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=3.80 min.

Example 64 Preparation of 2-[2-(S orR)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[4-(piperidin-2-yl)cylohexyl]eth-1-yl}acetamide

2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[4-(pyrid-2-yl)phenyl]eth-1-yl}acetamide(15 mgs, 0.02 mmol) was dissolved in MeOH (5 mL) and transferred to aParr hydrogenation bottle. PtO2 (50 mgs) and AcOH (2 mL) were added andthe mixture was hydrogenated at 40 psi overnight. The reaction mixturewas filtered through celite and condensed under reduced pressure. Theresulting material was purified by preparative HPLC (CH₃CN—H₂O-0.1% TFA)to afford the title compound as a single diastereomer.

¹H NMR (DMSO-d₆) δ=8.11 (1H, m), 7.59 (1H, d, J=7.8 Hz), 7.47 (1H, d,J=4.2 Hz), 7.34 (1H, t), 7.27 (1H, s), 7.21 (1H, t), 6.83 (1H, d, J=8.1Hz), 5.12 (1H, m), 3.70 (2H, m), 3.09 (3H, m), 2.42 (2H, m), 2.28 (3H,s), 2.04 (3H, s) 1.90 (6H, m), 1.56 (1H, m);

MS m/z (M+H) 699;

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=2.73 min.

Example 65 Preparation of 2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[4-(piperidin-2-yl)cyclohexyl]eth-1-yl}acetamide

2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[4-(pyrid-2-yl)phenyl]eth-1-yl}acetamide(15 mgs, 0.02 mmol) was dissolved in MeOH (5 mL) and transferred to aParr hydrogenation bottle. PtO₂ (50 mgs) and AcOH (2 mL) were added andthe mixture was hydrogenated at 40 psi overnight. The reaction mixturewas filtered through celite and condensed under reduced pressure. Theresulting material was purified by preparative HPLC (CH₃CN—H₂O-0.1% TFA)to afford the title compound as a single diastereomer.

¹H NMR (CD₃OD) δ=8.23 (1H, m), 7.57 (1H, d, J=7.8 Hz), 7.49 (1H, s),7.30 (1H, t), 7.26 (1H, s), 7.20 (1H, t), 6.81 (1H, d, J=6.6 Hz), 5.11(1H, m), 3.88 (1H, m), 3.56 (3H, m), 3.09 (2H, m), 2.28 (3H, s), 2.05(3H, s), 1.56 (1H, m);

MS m/z (M+H) 699;

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=2.89 min.

Example 66 Preparation of 2-[2-(S orR)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[4-(N-methyl-1,2,3,6-tetrahydropyridin-6-yl)phenyl]eth-1-yl}acetamide

The title compound was synthesized from 2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[4-(pyrid-2-yl)phenyl]eth-1-yl}acetamideusing Method F′ followed by Method G′.

¹H NMR (CD₃OD) δ=7.59 (1H, d, J=9.0 Hz), 7.51 (1H, s), 7.23 (7H, m),6.82 (1H, d, J=7.8 Hz), 5.80 (2H, dd), 5.07 (1H, m), 3.67 (1H, m), 2.90(4H, m), 2.39 (3H, m), 2.28 (3H, s), 2.03 (3H, s), 1.90 (2H, m), 1.67(3H, m), 0.91 (5H, m);

¹³C NMR (CD₃OD) δ=168.04, 136.66, 136.10, 134.31, 133.83, 132.86,132.42, 131.94, 129.23, 128.63, 128.26, 127.63, 124.85, 123.18, 115.53,59.98, 56.52, 52.54, 37.23, 36.03, 34.33, 25.17, 23.54, 19.29, 18.50,17.79, 12.90;

MS m/z (M+H) 705;

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=2.85 min.

Example 67 Preparation of 2-[2-(S orR)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,5,6-tetrahydroquinoxalin-2-yl]-N-{1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[4-(N-methyl-1,2,5,6-tetrahydropyridin-6-yl)phenyl]eth-1-yl}acetamide

The title compound was synthesized from 2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[4-(pyrid-2-yl)phenyl]eth-1-yl}acetamideusing Method F′ followed by Method G′.

¹H NMR (CD₃OD) δ=7.53 (1H, s), 7.31 (7H, m), 7.15 (1H, t), 6.82 (1H, d,J=7.8 Hz), 5.81 (2H, dd), 5.08 (1H, m), 3.61 (2H, m), 3.00 (4H, m), 2.40(3H, m), 2.29 (3H, s), 2.03 (3H, s), 1.86 (2H, m), 1.69 (2H, m), 0.91(4H, m);

MS m/z (M+H) 705;

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=2.74 min.

Example 68 2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R-[pyrrolidin-N-ylcarbonyl]-2-[4-(pyridin-4-yl)phenyl]eth-1-yl}acetamide

The title compound was prepared from compound 1061 and 4-pyridylstannane using Method D′, followed by deprotection using Method P,followed by coupling with2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid using Method I. The resulting material was purified by preparativeHPLC (CH₃CN—H₂O-0.1% TFA) to afford the title compound as a singlediastereomer.

¹H NMR (CD₃OD) δ=8.78 (2H, d, J=6.6 Hz), 8.41 (1H, d, J=8.1 Hz), 8.27(2H, d, J=6.6 Hz), 7.97 (2H, d, J=8.4 Hz), 7.56 (2H, d, J=8.1 Hz), 7.45(1H, d, J=6.6 Hz), 7.31 (3H, m), 7.07 (1H, t), 6.80 (1H, d, J=7.8 Hz),5.03 (2H, m), 3.71 (1H, m), 3.46 (1H, m), 3.20 (1H, m), 3.08 (1H, m),2.36 (2H, m), 2.27 (3H, s), 2.01 (3H, s), 1.83 (2H, m) 1.31 (2H, m);

MS m/z (M+H) 687;

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=2.95 min.

Example 69 Preparation of 2-[2-(S orR)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[4-(pyridin-4-yl)phenyl]eth-1-yl}acetamide

The title compound was prepared from compound 1061 and 4-pyridylstannane using Method D′, followed by deprotection using Method P,followed by coupling with2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetra-hydroquinoxalin-2-yl]aceticacid using Method I. The resulting material was purified by preparativeHPLC (CH₃CN—H₂O-0.1% TFA) to afford the title compound as a singlediastereomer.

¹H NMR (CD₃OD) δ=8.76 (2H, d, J=5.7 Hz), 8.41 (1H, d, J=8.7 Hz), 8.19(2H, d, J=5.4 Hz), 7.87 (2H, d, J=8.1 Hz), 7.57 (2H, d, J=9.3 Hz), 7.49(3H, m), 7.33 (1H, t), 7.25 (1H, s), 7.19 (1H, t), 6.81 (1H, d, J=8.1Hz), 5.05 (2H, m), 3.77 (1H, m), 3.53 (2H, m), 3.15 (2H, m), 2.99 (1H,m), 2.37 (2H, m), 2.27 (3H, s), 2.03 (3H, s), 1.79 (2H, m), 1.31 (2H,m);

MS m/z (M+H) 687;

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=3.13 min.

Example 70 Preparation of 2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[(N-methyl-1,2,5,6-tetrahydropyridin-4-yl)-phen-4-yl]eth-1-yl}acetamide

The title compound was synthesized from 2-[2-(S orR)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[4-(pyridin-4-yl)phenyl]eth-1-yl}acetamideusing Method J. The resulting solid was purified by preparative HPLC(CH₃CN—H₂O-0.1% TFA) to afford the title compound as a singlediastereomer.

¹H NMR (CD₃OD) δ=8.35 (1H, d, J=6.0 Hz), 7.57 (1H, d, J=9.3 Hz), 7.45(3H, m), 7.29 (5H, m), 6.81 (1H, d, J=9.3 Hz), 6.15 (1H, m), 5.05 (2H,m), 4.04 (1H, m), 3.73 (3H, m), 3.53 (2H, m), 3.02 (3H, s), 2.89 (3H,m), 2.28 (3H, s), 2.03 (3H, s), 1.94 (1H, m), 1.76 (2H, m);

MS m/z (M+H) 705;

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=2.85 min.

Example 71 Preparation of 2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[(N-methyl-1,2,5,6-tetrahydropyridin-4-yl)-phen-4-yl]eth-1-yl}acetamide

The title compound was synthesized from 2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzene-sulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[4-(pyridin-4-yl)phenyl]eth-1-yl}acetamideusing Method J. The resulting solid was purified by preparative HPLC(CH₃CN—H₂O-0.1% TFA) to afford the title compound as a singlediastereomer.

¹H NMR (CD₃OD) δ=8.34 (1H, d, J=7.8 Hz), 7.50 (3H, m), 7.31 (5H, m),7.11 (1H, t), 6.81 (1H, d, J=9.3 Hz), 6.17 (1H, m), 5.06 (2H, m), 4.04(1H, m), 3.56 (3H, m), 3.09 (3H, s), 2.37 (2H, m), 2.28 (3H, s), 2.03(3H, s), 1.80 (4H, m);

MS m/z (M+H) 705;

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=2.69 min.

Example 72 Preparation of 2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-[(R)-(pyrrolidin-N-ylcarbonyl)]-2-[(N-(methylpyrid-2-yl)phen-4-yl]eth-1-yl}acetamideiodide salt

The title compound was synthesized from 2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[4-(pyrid-2-yl)phenyl]eth-1-yl}acetamideusing Method F′.

¹H NMR (DMSO-d₆) δ=9.1 (1H, d, J=6.9 Hz), 8.62 (1H, t), 8.46 (1H, d,J=8.7 Hz), 8.14 (1H, t), 8.02 (1H, d, J=8.1 Hz), 7.55 (2H, d, J=8.4 Hz),7.41 (9H, m), 7.14 (1H, t), 6.82 (1H, d, J=8.1 Hz), 4.80 (2H, m), 4.10(3H, s), 3.57 (1H, m), 3.16 (1H, m), 3.03 (1H, m), 2.77 (2H, m), 2.19(3H, s), 1.98 (3H, s), 1.79 (3H, m);

MS m/z (M+H) 701;

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=3.41 min

Example 73 Preparation of 2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-[(R)-(pyrrolidin-N-ylcarbonyl)]-2-[N-(methylpyrid-4-yl)phen-4-yl]eth-1-yl}acetamideiodide salt

2-[2-(S orR)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[4-(pyridin-4-yl)phenyl]eth-1-yl}acetamide(300 mg, 0.4 mmol) was dissolved in MeOH (5 mL) and to it added MeI (5mL). The mixture was stirred at room temperature overnight. The solventwas removed under reduced pressure and the resulting solid purified viacolumn chromatography (silica gel) eluted with CH₂Cl₂—MeOH, 9:1 toafford the title compound.

¹H NMR (DMSO-d₆) δ=10.50 (1H, s), 8.99 (2H, d), 8.49 (3H, d), 8.00 (2H,d), 7.36 (5H, m), 7.16 (1H, t), 6.85 (1H, d), 4.82 (2H, m), 4.34 (3H,s), 3.59 (1H, m), 3.05 (1H, m), 2.75 (2H, m), 2.24 (3H, s), 2.08 (3H,s), 1.81 (3H, m);

MS m/z (M+1) 701;

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=3.09 min.

Example 74 Preparation of 2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-[(R)-(pyrrolidin-N-ylcarbonyl)]-2-[1-(piperidin-2-yl)phen-4-yl]eth-1-yl}acetamide

2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[4-(pyrid-2-yl)phenyl]eth-1-yl}acetamide(52 mgs, 0.076 mmol) was dissolved in AcOH (3 mL) and transferred to aParr hydrogenation bottle. PtO₂ (50 mg) was added and the mixture washydrogenated at 40 psi for 1 h. The reaction mixture was filteredthrough celite and reduced under vacuum to afford the title compound.

¹H NMR (DMSO-d₆) δ=8.37 (1H, d), 7.25 (9H, m), 6.83 (1H, t), 4.84 (1H,m), 4.60 (1H, m), 3.00 (5H, m), 2.62 (1H, m), 231 (3H, s), 1.99 (3H, s),1.86 (4H, s), 1.64 (3H, m), 1.30 (2H, m), 1.24 (2H, m);

MS m/z (M+H) 693.2;

HPLC (CH₃CN—H₂-0.1% TFA): R_(t)=3.18 min.

Example 75 Preparation of2-[2-(R,S)-1-(2-chloro-4-methylpyrid-5-ylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl)acetamide

2-Chloro-4-methyl-5-nitropyridine (1 g, 5.8 mmol) was dissolved in EtOH(60 mL). AcOH (4 mL) and Fe (5 eq.) were added and the mixture wasrefluxed at 80° C. overnight. The mixture was filtered through celiteand reduced under vacuum to afford the crude5-amino-2-chloro-4-methylpyridine which was used in the next step withno further purification. The amine was dissolved in conc. HCl (6 mL),transferred to a 3-neck round bottom flask, and cooled to −5° C. Asolution of NaNO₂/H₂O (440 mgs/5 μL) was slowly added and the mixturewas allowed to stir for 10 mins. To a second, separate 3-neck roundbottom flask was added H₂O (12 mL) and cooled to −5° C. Thionyl chloride(4.5 eq.) was then added dropwise. After complete addition the mixturewas allowed to warm to room temp. Whereupon CuCl (0.05 eq.) was addedand the mixture was then cooled back down to −5° C. The first reactionmixture, containing the amine precursor, was slowly added to the secondreaction mixture. A froth formed and was filtered off to afford6-chloro-4-methyl-pyridine-3-sulfonyl chloride which was used in thenext step with no further purification. The title compound wassynthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]-N-(pyrid-4-yl)ethylacetamide and 6-chloro-4-methyl-pyridine-3-sulfonyl chloride usingMethod G.

MS m/z (M+H) 501.4;

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=2.05 min.

Example 76 Preparation of 2-[2-(R orS)-1-(4-chloro-2,5-dimethylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-y]-4-methyl-N-{1-[(R)-pyrrolidin-N-ylcarbonyl)-2-[4-(N-methyl-pyrid-4-yl)phen-1-yl)eth-1-yl]}acetamideiodide salt

The TFA salt of 2-[2-(S orR)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[4-(pyridin-4-yl)phenyl]eth-1-yl}acetamidewas dissolved in EtOH/1N HCl to form a clear solution. The solution wasmade alkaline using saturated K₂CO₃ and extracted with CHCl₃. Thesolvent was removed in vacuo to afford the free base of 2-[2-(S orR)-1-(4-chloro-2,5-dimethylbenzene-sulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{-(R)-[pyrrolidin-N-ylcarbonyl]-2-[4-(pyridin-4-yl)phenyl]eth-1-yl}acetamide(130 mgs, 0.19 mmol) which was dissolved in MeOH (3 mL) and to it wasadded MeI (3 mL) and the mixture was allowed to stir for 1 week. Theresulting solid was purified by preparative HPLC (CH₃CN—H₂O-0.1% TFA toafford the title compound.

¹H NMR (DMSO-d₆) δ=8.96 (1H, d, J=6.9 Hz), 8.46 (2H, d, J=6.9 Hz), 7.97(1H, d, J=8.1 Hz), 7.39 (9H, m), 7.13 (1H, d, J=8.1 Hz), 4.94 (1H, m),4.78 (1H, m), 4.31 (3H, s), 3.58 (2H, m), 2.75 (1H, m), 2.71 (3H, s),2.27 (3H, s), 1.93 (3H, s), 1.79 (3H, m);

MS m/z (M+H) 715.2;

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=3.32 min.

Example 77 Preparation of2-[2-(R)-1-(2,4,6-trimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-benzylacetamide

The title material was obtained from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]-N-benzylacetamideand 2,4,6-trimethylphenyl sulfonyl chloride using Method G, followed bya chiral HPLC separation.

MS (ES): m/e 478.1 (M).

Example 78 Preparation of2-[2-(R,S)-1-(p-toluenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-benzylacetamide

The title material was obtained from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]-N-benzylacetamideand 4-methylphenyl sulfonyl chloride using Method G.

MS (ES): m/e 436 (M).

Example 79 Preparation of2-[2-(R,S)-1-(p-toluenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(2-methoxyphenyl)acetamide

The title material was purchased from Maybridge

Example 80 Preparation of2-[2-(R,S)-1-(p-toluenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(2-ethoxyphenyl)acetamide

The title material was purchased from Specs.

Example 81 Preparation of2-[2-(R,S)-1-(2,4,6-trimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-phenylacetamide

The title material was prepared from2-[2-(R,S)-1-(2,4,6-trimethyl-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and aniline using Method C.

MS (ES): m/e 464 (M).

Example 82 Preparation of2-[2-(R,S)-1-(2,5-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-benzylacetamide

The title material was obtained from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]-N-benzylacetamideand 2,5-dichlorophenyl sulfonyl chloride using Method G.

MS (ES): m/e 504 (M).

Example 83 Preparation of2-[2-(R,S)-1-(3,5-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-benzylacetamide

The title material was obtained from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]-N-benzylacetamideand 3,5-dichlorophenyl sulfonyl chloride using Method G.

MS (ES): m/e 504 (M).

Example 84 Preparation of2-[2-(R,S)-1-(2,3-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-benzylacetamide

The title material was obtained from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]-N-benzylacetamideand 2,3-dichlorophenyl sulfonyl chloride using Method G.

MS (ES): m/e 504 (M).

HPLC (H₂O-acetonitrile-0.1% TFA): R_(t)=27.16 min.

Example 85 Preparation of2-[2-(R,S)-1-(2,3-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-methylacetamide

2-[2-(R,S)-1-(2,3-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]aceticacid was coupled to methyl amine HCl using Method C.

HPLC (H₂O-acetonitrile-0.1% TFA): R_(t)=20.98 min.

Example 86 Preparation of2-[2-(R,S)-1-(2,3-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-cyclohexylmethylacetamide

2-[2-(R,S)-1-(2,3-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]aceticacid was coupled to cyclohexanemethylamine using Method C.

HPLC (H₂O-acetonitrile-0.1% TFA): R_(t)=30.02 min.

Example 87 Preparation of2-[2-(R,S)-1-(2,4-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-benzylacetamide

The title material was obtained from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]-N-benzylacetamideand 2,4-dichlorophenyl sulfonyl chloride using Method G.

MS (ES): m/e 504 (M).

Example 88 Preparation of2-[2-(R,S)-1-(2-fluorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-benzylacetamide

The title material was obtained from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]-N-benzylacetamideand 2-fluorophenyl sulfonyl chloride using Method G.

HPLC (H₂O-acetonitrile-0.1% TFA): R_(t)=24.12 min.

Example 89 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-benzylacetamide

The title material was obtained from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]-N-benzylacetamideand 2,5-dimethyl 4-chlorophenyl sulfonyl chloride using Method G.

HPLC (H₂O-acetonitrile-0.1% TFA): R_(t)=29.46 min.

Example 90 Preparation of2-[2-(R,S)-1-(2,3,4-trichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-benzylacetamide

The title material was obtained from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]-N-benzylacetamideand 2,3,4-trichlorophenylsulfonyl chloride using Method G.

HPLC (H₂O-acetonitrile-0.1% TFA): R_(t)=29.56 min.

Example 91 Preparation of2-[2-(R,S)-1-(2,3-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-phenylacetamide

2-[2-(R,S)-1-(2,3-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]aceticacid was coupled to aniline using Method C.

HPLC (H₂O-acetonitrile-0.1% TFA): R_(t)=27.7 min.

Example 92 Preparation of2-[2-(S)-1-(2,4,6-trimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-benzylacetamide

The title material was obtained from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]-N-benzylacetamideand 2,4,6-trimethylphenyl sulfonyl chloride using Method G, followed bya chiral HPLC separation.

MS (ES): m/e 478.1 (M).

Example 93 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]acetamide

The title material was prepared from 1,2-phenylenediamine and maleimideusing Method F, followed by Method G using 4-chloro 2,5-dimethylphenylsulfonyl chloride.

MS (ES): m/e 408 (M+H)

Example 94 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(indol-3-yl)-1-(S)-(methoxycarbonyl)eth-1-yl]acetamide

The title compound was prepared using Method Y starting with2-(indol-3-yl)-1-(S)-(methoxycarbonyl)-1-aminoethane and2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid.

MS (ES): m/e 610 (M+H).

Example 95 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(t-butoxycarbonyl)-3-methylprop-1-yl]acetamide

The title compound was prepared from2-[2-(R,S)-1-4-(chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and D-isoleucine t-butyl ester using Method Y.

HPLC (water-acetonitrile-0.1% TFA): R_(t)=35.38 min

Example 96 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-methylenecarbonyl-[3-(R)-t-butoxycarboxamide-pyrrolidin-N-yl]

The title compound was prepared from2-[2-(R,S)-1-4-(chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and 3-(R)-t-butoxycarboxamide pyrrolidine using Method W.

MS (ES): m/e 599.2 (M+Na)

Example 97 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-methylenecarbonyl-[2-(S)-carboxamidepyrrolidin-N-yl]

The title compound was prepared from2-[2-(R,S)-1-4-(chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and 2-(S)-carbox-amide pyrrolidine using Method W.

MS (ES): m/e 527.1 (M+Na)

Example 98 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-methylenecarbonyl-[3-(R,S)-hydroxy-pyrrolidin-N-yl]

The title compound was prepared from2-[2-(R,S)-1-4-(chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and 3-(R,S)-hydroxypyrrolidine using Method W.

MS (ES): m/e 500.1 (M+Na).

Example 99 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N,N-(dipyrid-3-ylmethyl)acetamide

The title compound was prepared from2-[2-(R,S)-1-4-(chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and N,N-dipyrid-3-ylmethylamine using Method W.

MS (ES): m/e 590.2 (M)

Example 100 Preparation of 2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(pyrrolidin-N-ylcarbonyl)-2-(4-amidino)phenyl-eth-1-yl]acetamide

The title material was obtained from2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]-N-[2-(4-cyanophenyl)-1-(R)-(pyrrolidin-N-ylcarbonyl)eth-1-yl]acetamideand ammonium acetate using Method T. The desired diastereomer wasobtained upon prep HPLC purification.

HPLC (acetonitrile/water-0.1% TFA): R_(t)=3.90 min.

MS (ES): m/e 652 (M+H).

Example 101 Preparation of 2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(pyrrolidin-N-ylcarbonyl)-2-(4-amidino)phenyl-eth-1-yl]acetamide

The title material was obtained from2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-cyanophenyl)-1-(R)-(pyrrolidin-N-ylcarbonyl)eth-1-yl]acetamideand ammonium acetate using Method T. The desired diastereomer wasobtained upon prep HPLC purification.

HPLC (acetonitrile/water-0.1% TFA): R_(t)=3.60 min.

MS (ES): m/e 652 (M+H).

Example 102 Preparation of 2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R)-[pyrrolidin-N-ylcarbonyl]-2[N-(phenyl)-piperidin-4-yl)]eth-1-yl}acetamide

N-phenylation ofN-Boc-1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[N-(piperidin-4-yl]ethylamineusing Method M, followed by deprotection using Method P, and subsequentcoupling to2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzene-sulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid using Method S, led to the desired material, which was purified byprep HPLC.

HPLC (acetonitrile/water-0.1% TFA): R_(t)=4.15 min.

MS (ES): m/e 693 (M+H).

Example 103 Preparation of 2-[2-(S orR)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[N-(phenyl)-piperidin-4-yl)]eth-1-yl}acetamide

N-phenylation ofN-Boc-1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[N-(piperidin-4-yl]ethylamineusing Method M, followed by deprotection using Method P, and subsequentcoupling to2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]aceticacid using Method S, led to the desired material, which was purified byprep HPLC.

HPLC (acetonitrile/water-0.1% TFA): R_(t)=4.27 min.

MS (ES): m/e 693 (M+H).

Example 104 Preparation of 2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[N-(pyridin-4-yl)-piperidin-4-yl]eth-1-yl}acetamide

Coupling of N-phenylation ofN-Boc-1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[N-(piperidin-4-yl]ethylaminewith 4-chloropyridine using Method N, followed by deprotection usingMethod P, and subsequent coupling to2-[2-(R,S)-1-(4-chloro-2,5-di-methylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid using Method S, led to the desired material, which was purified byprep HPLC.

HPLC (acetonitrile/water-0.1% TFA): R_(t)=2.16 min.

MS (ES): m/e 695 (M+H).

Example 105 Preparation of 2-[2-(S orR)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[N-(pyridin-4-yl)-piperidin-4-yl]eth-1-yl}acetamide

Coupling of N-phenylation ofN-Boc-1-(R)-[pyrrolidin-N-ylcarbonyl]-2-[N-(piperidin-4-yl]ethylaminewith 4-chloropyridine using Method N, followed by deprotection usingMethod P, and subsequent coupling to2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]aceticacid using Method S, led to the desired material, which was purified byprep HPLC.

HPLC (acetonitrile/water-0.1% TFA): R_(t)=2.77 min.

MS (ES): m/e 695 (M+H).

Example 106 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[3-(2-methylthiazol-4-yl)-pyrazol-5-yl]acetamide

2-[2-(R,S)-1-(4-Chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid was coupled with2-tert-Butyl-5-(2-methyl-thiazol-4-yl)-2H-pyrazol-3-ylamine in presenceof POCl₃ in pyridine at −20° C. for 5 min, then at room temperature for18 h. The reaction mixture was poured on ice, and crude product wasfiltered off. Pure product, obtained after recrystallization from MeOH,was treated with formic acid at reflux temperature for 4 h. Excessformic acid was removed and crude product purified by recrystallizationwith ethyl acetate to afford the title compound as a white solid.

¹H NMR (DMSO-d₆): δ=1 99 (s, 3H), 2.20(s, 3H), 2.42-2.46, (br. s, 2H),2.68(s, 3H), 4.94(dd, 1H, J=6 Hz), 6.81(s, 1H), 7.45(s, 1H),6.84-7.39(m, Ar—H, 6H), 7.79(s, 1H, NH), 10.43, 10.51 (s, 1H)

MS (ES): m/e 571.1(M);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=5.12 min.

Example 107 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(N-morpholinocarbonyl)piperidin-4-yl]eth-1-yl}acetamide

The title compound was prepared from2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(2-piperidin-4-yl)-eth-1-ylacetamide and morpholine carbonyl chloride using Method J′.

MS (ES): m/e (M) 632.2

Example 108 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-[(thiohen-2-yl)methylenecarbonyl]piperidin-4-yl]eth-1-yl}acetamide

The title compound was prepared by Method J′ using thiophen-2-yl acetylchloride and2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(2-piperidin-4-yl)-eth-1-ylacetamide.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=11.07 min.

MS (ES): m/e (M+H+) 644.

Example 109 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(3,5-dimethyloxazol-4-ylcarbonyl)piperidin-4-yl]eth-1-yl}acetamide

The title compound was prepared by Method J′ using3,5-dimethyl-isoxazol-4-ylcarbonyl chloride and2-[2-(R,S)-1-(4-chloro-2,5-dimethyl-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(2-piperidin-4-yl)-eth-1-ylacetamide.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=10.596 min.

MS (ES): m/e (M+H+) 643.

Example 110 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[(N-furan-2-ylcarbonyl)piperidin-4-yl]eth-1-yl]acetamide

The title compound was prepared by Method J′, using furan-2-ylcarbonylchloride and2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(2-piperidin-4-yl)-eth-1-ylacetamide.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=10.852 min.

MS (ES): m/e (M+H+) 614.

Example 111 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(isoxazol-5-yl-carbonyl)piperidin-4-yl]eth-1-yl}acetamide

The title compound was prepared by Method J′, usingisoxazol-5-ylcarbonyl chloride and2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(2-piperidin-4-yl)-eth-1-ylacetamide.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=10.598 min.

MS (ES): m/e (M+H+) 615

Example 112 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(5-methylpyrazol-3-yl-carbonyl)piperidin-4-yl]eth-1-yl}acetamide

The title compound was prepared by Method J′, using5-methylpyrazol-3-ylcarbonyl chloride and2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(2-piperidin-4-yl)-eth-1-ylacetamide.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=9.695 min.

MS (ES): m/e (M+H+) 628.

Example 113 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(1-methyl-3-t-butylpyrazol-5-yl-carbonyl)piperidin-4-yl]eth-1-yl}acetamide

The title compound was prepared by Method J′, using1-methyl-3-t-butylpyrazol-5-ylcarbonyl chloride and2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(2-piperidin-4-yl)-eth-1-ylacetamide.

HPLC (CH₃CN—H₂O-0.1% TFA):R_(t)=11.759 min.

MS (ES): m/e (M+H+) 684.

Example 114 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(4-methylthiadiazol-5-yl-carbonyl)piperidin-4-yl]eth-1-yl}acetamide

The title compound was prepared by Method J′ using4-methyl-2,3-thiadiazole-5-carbonyl chloride and2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(2-piperidin-4-yl)-eth-1-ylacetamide.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=10.831 min.

MS (ES): m/e (M+H+) 646.

Example 115 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(chloromethylene-carbonyl)piperidin-4-yl]eth-1-yl}acetamide

The title compound was prepared by Method J′, using chloroacetylchloride and2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(2-piperidin-4-yl)-eth-1-ylacetamide.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=10.663 min.

MS (ES): m/e (M+H+) 596.

Example 116 Preparation of 2-[2-(R,S)-1(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(phenylcarbonyl)-piperidin-4-yl]eth-1-yl}acetamide

The title compound was prepared by Method J′, using phenyl chloroformateand2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(2-piperidin-4-yl)-eth-1-ylacetamide.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=11.231 min.

MS (ES): m/e (M+H+) 624

Example 117 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(isopropylcarbonyl)piperidin-4-yl]eth-1-yl}acetamide

The title compound was prepared by Method J′, using isopropyl carbonylchloride and2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(2-piperidin-4-yl)-eth-1-ylacetamide.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=10.922 min.

MS (ES): m/e (M+H+) 590.2.

Example 118 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(t-butylmethylene-carbonyl)piperidin-4-yl]eth1-yl}acetamide

The title compound was prepared by Method J′, using t-butylacetylchloride and2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzene-sulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(2-piperidin-4-yl)-eth-1-ylacetamide.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=11.745 min.

MS (ES): m/e (M+H+) 618.

Example 119 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(2-phenylethenyl-carbonyl)piperidin-4-yl]eth-1-yl}acetamide

The title compound was prepared by Method J′, using cinnamyl chlorideand2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(2-piperidin-4-yl)-eth-1-ylacetamide.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=11.894 min.

MS (ES): m/e (M+H+) 650.

Example 120 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(methoxymethylene-carbonyl)piperidin-4-yl]eth-1-yl}acetamide

The title compound was prepared by Method J′, using methoxy acetylchloride and2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(2-piperidin-4-yl)-eth-1-ylacetamide.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=11.853 min.

MS (ES): m/e (M+H+) 592.

Example 121 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(pyrazin-2-ylcarbonyl)piperidin-4-yl]eth-1-yl}acetamide

The title compound was prepared by Method J′, using pyrazin-2-ylcarbonylchloride and2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(2-piperidin-4-yl)-eth-1-ylacetamide.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=10.036 min.

MS (ES): m/e (M+H+) 626

Example 122 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(isoquinolin-3-ylcarbonyl)piperidin-4-yl]eth-1-ylacetamide

The title compound was prepared by Method J′, usingisoquinolin-3-ylcarbonyl chloride and2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(2-piperidin-4-yl)-eth-1-ylacetamide.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=10.408 min.

MS (ES): m/e (M+H+) 675

Example 123 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(pyrrolidin-5-one-2-ylcarbonyl)piperidin-4-yl]eth-1-yl}acetamide

The title compound was prepared by Method J′ using2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]N-(2-piperidin-4-yl)-eth-1-ylacetamide and N-pyrrolidin-5-one-2-ylcarbamyl chloride.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=9.403 min.

MS (ES): m/e (M+H+) 631 (M+Na+) 653

Example 124 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(N′-acetylpyrrolidin-2-ylcarbonyl)piperidin-4-yl]eth-1-yl}acetamide

The title compound was prepared by Method J′, usingN-acetylpyrrolidin-2-ylcarbonyl chloride and2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(2-piperidin-4-yl)-eth-1-ylacetamide.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=9.797 min.

MS (ES): m/e (M+H+) 659 (M+Na+) 681.

Example 125 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)]-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(dichloromethylenecarbonyl)piperidin-4-yl]eth-1-yl}acetamide

The title compound was prepared by Method J′, using dichloroacetylchloride and2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(2-piperidin-4-yl)-eth-1-ylacetamide.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=11.177 min.

MS (ES): m/e (M+H+) 631 (M+Na+) 652.

Example 126 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(ethylcarbonyl)piperidin-4-yl]eth-1-yl}acetamide

The title compound was prepared by Method J′, using propionyl chlorideand2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(2-piperidin-4-yl)-eth-1-ylacetamide.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=10.467 min.

MS (ES): m/e (M+H+) 576 (M+Na+) 598.

Example 127 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(n-propylcarbonyl)piperidin-4-yl]eth-1-yl}acetamide

The title compound was prepared by Method J′, using butyryl chloride and2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(2-piperidin-4-yl)-eth-1-ylacetamide.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=10.733 min.

MS (ES): m/e (M+H+) 590

Example 128 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[4-[N-(pyrazin-2-ylcarbonyl)amino]pheneth-1-yl}acetamide

The title compound was prepared by Method I′ using pyrazin-2-yl carbonylchloride and2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-2-(4-aminophenyl)eth-1-ylacetamide.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=10.873 min.

MS (ES): m/e (M+H+) 634 (M+Na+) 656.

Example 129 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(isoquinolin-2-yl-carbonyl)amino]pheneth-1-yl}acetamide

The title compound was prepared using Method I′, starting with2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]-N-2-(4-aminophenyl)eth-1-ylacetamideand isoquinolin-2-ylcarbonyl chloride.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=12.312 min.

MS (ES): m/e (M+H+) 683 (M+Na+) 705.

Example 130 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(N′-acetylpyrrolidin-2-yl-carbonyl)amino]pheneth-1-yl}acetamide

The title compound was prepared using Method I′ starting with2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-aminophenyl)eth-1-yl]acetamideand N-acetylpyrrolidin-2-ylcarbonyl chloride.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=10.071 min.

MS (ES): m/e (M+H+) 667 (M+Na+) 689.

Example 131 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(1,2-benzothiadiazol-5-ylcarbonyl)amino]pheneth-1-yl}acetamide

The title compound was prepared using Method I′ starting with2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-aminophenyl)eth-1-yl]acetamideand 1,2-benzothiadiazol-5-ylcarbonyl chloride.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=11.549 min.

MS (ES): m/e (M+H+) 690 (M+Na+) 712.

Example 132 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(benzofuran-5-ylcarbonyl)amino]pheneth-1-yl}acetamide

The title compound was prepared using Method I′ starting with2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-aminophenyl)eth-1-yl]acetamideand benzofuran-5-ylcarbonyl chloride.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=11.325 min.

MS (ES): m/e (M+H+) 674 (M+Na+) 696.

Example 133 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(3-methylisoxazol-5-ylcarbonyl)amino]pheneth-1-yl}acetamide

The title compound was prepared using Method I′ starting with2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-aminophenyl)eth-1-yl]acetamideand 3-methylisoxazol-5-ylcarbonyl chloride.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=10.346 min.

MS (ES): m/e (M+H+) 637 (M+Na+) 659.

Example 134 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(N′-morpholinocarbonyl)amino]pheneth-1-yl}acetamide

The title compound was prepared using Method I′ starting with2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-aminophenyl)eth-1-yl]acetamideand morpholinocarbonyl chloride.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=10.203 min.

MS (ES): m/e (M+H+) 641 (M+Na+) 663

Example 135 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(methoxyphen-3-ylcarbonyl)amino]pheneth-1-yl}acetamide

The title compound was prepared using Method I′ starting with2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-aminophenyl)eth-1-yl]acetamideand 3-methoxy benzoyl chloride.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=11.506 min.

MS (ES): m/e (M+H+) 662 (M+Na+) 684.

Example 136 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(thiophen-2-ylmethylenecarbonyl)amino]pheneth-1-yl}acetamide

The title compound was prepared using Method I′ starting with2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-aminophenyl)eth-1-yl]acetamideand thiophen-2-ylacetyl chloride.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=11.273 min.

MS (ES): m/e (M+H+) 652 (M+Na+) 674.

Example 137 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(3,5-dimethylisoxazol-4-ylcarbonyl)amino]pheneth-1-yl}acetamide

The title compound was prepared using Method I′ starting with2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-aminophenyl)eth-1-yl]acetamideand 3,5-dimethylisoxazol-4-ylcarbonyl chloride.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=10.943 min.

MS (ES): m/e (M+H+) 651 (M+Na+) 673.

Example 138 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(2-(pyrid-3-yl)ethylcarbonyl)amino]pheneth-1-yl}acetamide

The title compound was prepared using Method I′ starting with2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-aminophenyl)eth-1-yl]acetamideand pyridin-3-ylpropionyl chloride.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=8.807 min.

MS (ES): m/e (M+H+) 661 (M+Na+) 683.

Example 139 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(furan-2-ylcarbonyl)-amino]pheneth-1-yl}acetamide

The title compound was prepared using Method I′ starting with2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]-N-[2-(4-aminophenyl)eth-1-yl]acetamideand furan-2-ylcarbonyl chloride.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=10.39 min.

MS (ES): m/e (M+H+) 622 (M+Na+) 644.

Example 140 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(isoxazol-5-ylcarbonyl)amino]pheneth-1-yl}acetamide

The title compound was prepared using Method I′ starting with2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-aminophenyl)eth-1-yl]acetamideand isoxazol-5-ylcarbonyl chloride.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=10.738 min.

MS (ES): m/e (M+H+) 623 (M+Na+) 645.

Example 141 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(3-methylpyrazol-5-yl-carbonyl)amino]pheneth-1-yl}acetamide

The title compound was prepared using Method I′ starting with2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-aminophenyl)eth-1-yl]acetamideand 3-methylpyrazol-5-ylcarbonyl chloride.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=10.466 min.

MS (ES): m/e (M+H+) 636 (M+Na+) 658.

Example 142 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(1-methyl-3-t-butylpyrazol-5-ylcarbonyl)amino]pheneth-1-yl}acetamide

The title compound was prepared using Method I′ starting with2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzene-sulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-aminophenyl)eth-1-yl]acetamideand 1-methyl-3-t-butylpyrazol-5-ylcarbonyl chloride.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=12.15 min.

MS (ES): m/e (M+H+) 692 (M+Na+) 714.

Example 143 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(4-methyl-1,2,3-thiadiazol-5-ylcarbonyl)amino]pheneth-1-yl}acetamide

The title compound was prepared using Method I′ starting with2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-aminophenyl)eth-1-yl]acetamideand 4-methyl-1,2,3-thiadiazole-5-carbonyl chloride.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=10.454 min.

MS (ES): m/e (M+H+) 654 (M+Na+) 676.

Example 144 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(chloromethylenecarbonyl)amino]pheneth-1-yl}acetamide

The title compound was prepared using Method I′ starting with2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzene-sulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-aminophenyl)eth-1-yl]acetamideand chloroacetyl chloride.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=10.755 min.

MS (ES): m/e (M+H+) 604 (M+Na+) 626.

Example 145 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(chlorophen-2-ylcarbonyl)amino]pheneth-1-yl}acetamide

The title compound was prepared by Method I′ starting with2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzene-sulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-aminophenyl)eth-1-yl]acetamideand 2-chlorobenzoyl chloride.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=11.549 min.

MS (ES): m/e (M+H+) 666 (M+Na+) 688.

Example 146 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(phenylcarbonyl)amino]pheneth-1-ylacetamide

The title compound was prepared by Method I′ starting with2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzene-sulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-aminophenyl)eth-1-yl]acetamideand benzoyl chloride.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=11.405 min.

MS (ES): m/e (M+H+) 632 (M+Na+) 654.

Example 147 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(isopropylcarbonyl)amino]pheneth-1-yl}acetamide

The title compound was prepared by Method I′ starting with2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzene-sulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-aminophenyl)eth-1-yl]acetamideand isobutyryl chloride.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=10.927 min.

MS (ES): m/e (M+H+) 598 (M+Na+) 620

Example 148 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(pyrid-2-ylcarbonyl)amino]pheneth-1-yl}acetamide

The title compound was prepared by Method I′ starting with2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzene-sulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-aminophenyl)eth-1-yl]acetamideand pyrid-2-yl carbonyl chloride.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=11.392 min.

MS (ES): m/e (M+H+) 633 (M+Na+) 655

Example 149 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(pyrid-4-ylcarbonyl)amino]pheneth-1-yl}acetamide

The title compound was prepared using Method I′ starting with2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzene-sulfonyl)-3-oxo-1,2,3,4-tetra-hydroquinoxalin-2-yl]-N-[2-(4-aminophenyl)eth-1-yl]acetamideand pyrid-4-ylcarbonyl chloride.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=9.53 min.

MS (ES): m/e (M+H+) 633 (M+Na+) 655.

Example 150 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(n-butylcarbonyl)amino]pheneth-1-yl}acetamide

The title compound was prepared using Method I′ starting with2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzene-sulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-aminophenyl)eth-1-yl]acetamideand pentanoyl chloride.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=11.4 min.

MS (ES): m/e (M+H+) 612 (M+Na+) 634.

Example 151 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(t-butylmethylenecarbonyl)amino]pheneth-1-yl}acetamide

The title compound was prepared using Method I′ starting with2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzene-sulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-aminophenyl)eth-1-yl]acetamideand t-butylacetyl chloride.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=11.655 min.

MS (ES): m/e (M+H+) 626 (M+Na) 648

Example 152 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(2-phenylethenylcarbonyl)amino]pheneth-1-yl}acetamide

The title compound was prepared using Method I′ starting with2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzene-sulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-aminophenyl)eth-1-yl]acetamideand cinnamoyl chloride.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=11.918 min.

MS (ES): m/e (M+H+) 658 (M+Na+) 680.

Example 153 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(fluorophen-2-ylcarbonyl)amino]pheneth-1-yl}acetamide

The title compound was prepared using Method I′ starting with2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzene-sulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-aminophenyl)eth-1-yl]acetamideand 2-fluorobenzoyl chloride.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=11.537 min.

MS (ES): m/e (M+H+) 650 (M+Na+) 672.

Example 154 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(methoxymethylenecarbonyl)amino]pheneth-1-yl}acetamide

The title compound was prepared using Method I′ starting with2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-aminophenyl)eth-1-yl]acetamideand methoxyacetyl chloride.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=10.432 min.

MS (ES): m/e (M+H+) 600 (M+Na+) 622.

Example 155 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(ethylcarbonyl)amino]pheneth-1-yl}acetamide

The title compound was prepared using Method I′ starting with2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-aminophenyl)eth-1-yl]acetamideand propionyl chloride.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=10.58 min.

MS (ES): m/e (M+H+) 584 (M+Na+) 606.

Example 156 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(propylcarbonyl)amino]pheneth-1-yl}acetamide

The title compound was prepared using Method I′ starting with2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-aminophenyl)eth-1-yl]acetamideand butyryl chloride.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=10.931 min.

MS (ES): m/e (M+H+) 598 (M+Na+) 620.

Example 157 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(dichloromethylenecarbonyl)amino]pheneth-1-yl}acetamide

The title compound was prepared using Method I′ starting with2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-aminophenyl)eth-1-yl]acetamideand dichloroacetyl chloride.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=11.307 min.

MS (ES): m/e (M+H+) 638 (M+Na+) 660.

Example 158 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{4-[N-(methylenedioxyphen-4-ylcarbonyl)amino]pheneth-1-y}acetamide

The title compound was prepared using Method I′ starting with2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-aminophenyl)eth-1-yl]acetamideand 3,4-methylenedioxybenzoyl chloride.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=11.48 min.

MS (ES): m/e (M+H+) 676 (M+Na+) 698.

Example 159 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(2-hydroxyeth-1-yl)acetamide

The title compound was synthesized from2-[(R,S)-1-(4-chloro-2,5-di-methylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and 2-aminoethanol using Method I.

¹H NMR (d₆-DMSO) δ=10.47 (s, 1H), 7.91 (t, J=7.8 Hz, 1H), 7.48 (s, 1H),7.43 (s, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.28 (t, J=7.8 Hz, 1H), 7.09 (t,J=7.8 Hz, 1H), 6.82 (d, J=7.8 Hz, 1H), 4.85 (dd, J=5.5, 8.8 Hz, 1H),3.34-3.30 (m, 2H), 3.07-3.03 (m, 2H), 2.29-2.13 (m, 5H), 2.01 (s, 3H).

Example 160 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(2-bromoeth-1-yl)acetamide

The title compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and 2-bromoethylamine using Method I.

¹H NMR (CDCl₃) δ=8.09 (s, 1H), 7.70 (d, J=8.2 Hz, 1H), 7.57(s, 1H),7.31-7.14 (m, 4H), 6.75 (d, J=8.2 Hz, 1H), 6.32 (bs, 1H), 5.09 (dd,J=4.4, 9.9 Hz, 1H), 3.63-3.34 (m, 4H), 2.56 (dd, J=4.4, 14.8 Hz, 1H),2.40 (dd, J=4.4, 14.8 Hz, 1H), 2.26 (s, 3H), 2.06 (s, 3H).

Example 161 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(imidazol-4-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-di-methylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and histamine using Method I.

¹H NMR (d₆-DMSO) δ=10.51 (s, 1H), 9.03 (s, 1H), 8.17 (t, J=7.5 Hz, 1H),7.45-7.41 (m, 3H), 7.34 (d, J=7.5 Hz, 1H), 7.28 (t, J=7.5 Hz, 1H), 7.10(t, J=7.5 Hz, 1H), 6.83 (d, J=7.5 Hz, 1H), 4.85 (dd, J=5.1, 9.9 Hz, 1H),3.33-3.25 (m, 2H), 2.73 (t, J=6.6 Hz, 2H), 2.29-2.08 (m, 5H), 1.98 (s,3H).

Example 162 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(indol-3-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-di-methylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and tryptamine using Method I and tryptamine.

¹H NMR (d₆-DMSO) δ=10.82 (s, 1H), 10.49 (s, 1H), 8.02 (t, J=5.6 Hz, 1H),7.50-7.25 (m, 6H), 7.14-6.95 (m, 4H), 6.83 (d, J=7.8 Hz, 1H), 4.89 (dd,J=5.1, 9.3 Hz), 3.33-3.21 (m, 3H), 2.75 (t, J=7.8 Hz, 2H), 2.29-2.13 (m,5H), 2.02 (s, 3H).

Example 163 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[(2-dimethylamino)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-di-methylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and N,N-dimethylethylenediamine using Method I.

¹H NMR (d₆-DMSO) δ=10.41 (s, 1H), 7.81 (t, J=7.8 Hz, 1H), 7.48-7.38 (m,2H), 7.27 (t, J=7.8 Hz, 1H), 7.09 (t, J=7.8 Hz, 1H), 6.82 (d, J=7.8 Hz,1H), 4.85 (dd, J=5.1, 8.7 Hz, 1H), 3.10-3.00 (m, 2H), 2.23-2.15 (m, 7H),2.11 (s, 6H), 2.02 (s, 3H).

Example 164 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[(4-methoxycarbonylphenyl)methylacetamide

The title compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-di-methylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and methyl (4-aminomethyl)benzoate using Method I.

Example 165 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]-N-(4-nitrobenzyl)acetamide

The title compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-di-methylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and 4-nitrobenzylamine using Method I.

¹H NMR (d₆-DMSO) δ=10.52 (s, 1H), 8.61 (t, J=7.8 Hz, 1H), 8.19 (d, J=8.7Hz, 2H), 7.54 (d, J=8.7 Hz, 2H), 7.46-7.42 (m, 3H), 7.29 (t, J=7.8 Hz,1H), 7.12 (t, J=7.8 Hz, 1H), 6.83 (d, J=7.8 Hz, 1H), 4.94 (dd, J=3.9,9.3 Hz, 1H), 4.50-4.42(m, 1H), 4.33-4.25 (m, 1H), 2.43-2.26 (m, 2H),2.22 (s, 3H), 1.99 (s, 3H).

Example 166 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(N-morpholino)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-di-methylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and 4-(2-aminoethyl)morpholine using Method I.

¹H NMR (d₆-DMSO) δ=10.45 (s, 1H0, 7.83 (t, J=7.8 Hz, 1H), 7.46-7.40 (m,3H), 7.28 (t, J=7.8 Hz, 1H0, 7.10 (t, J=7.8 Hz, 1H), 6.82 (d, J=7.8 Hz,1H), 4.85 (dd, J=4.8, 8.7 Hz, 1H), 3.56 (m, 4H), 3.18-3.00 (m, 2H),2.34-2.11(m, 1H), 2.01 (s, 3H).

Example 167 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-2-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-di-methylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and 2-aminoethylpyridine using Method I.

¹H NMR (d₆-DMSO) δ=10.48 (s, 1H), 8.78 (d, J=5.4 Hz, 1H), 8.45 (t, J=8.1Hz, 1H), 8.13 (t, J=7.8 Hz, 1H), 7.87 (t, J=8.1 Hz, 2H), 7.42 (d, J=5.4Hz, 2H), 7.34 (d, J=7.8 Hz, 1H), 7.27 (t, J=7.8 Hz, 1H), 7.09 (t, J=7.8Hz, 1H), 6.82 (d, J=7.8 Hz, 1H), 4.82 (dd, J=4.2, 8.7 Hz, 1H), 3.43-3.41(m, 2H), 3.13-3.08 (m, 2H), 2.26-2.06 (m, 5H), 1.97 (s, 3H).

Example 168 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(pyrid-2-ylmethyl)acetamide

The title compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-di-methylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and 2-aminomethylpyridine using Method I.

¹H NMR (d₆-DMSO) δ=10.56 (s, 1H), 8.97 (t, J=5.4 Hz, 1H), 8.77 (d, J=5.4Hz, 1H), 8.40 (t, J=7.8 Hz, 1H), 7.82 (t, J=7.8 Hz, 2H), 7.45-7.42 (m,3H), 7.30 (t, J=7.8 Hz, 1H), 7.11 (t, J=7.8 Hz, 1H), 6.84 (d, J=7.8 Hz,1H), 4.91 (dd, J=4.8, 9.9 Hz, 1H), 4.63-4.51 (m, 2H), 2.48-2.44 (m, 1H),2.34-2.26 (m, 1H), 2.22 (s, 3H), 1.97 (s, 3H).

Example 169 Preparation of2-[2-(R,S)-1-(napth-1-ylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-benzylacetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-benzylacetamidecondensed with 1-naphthalene-sulfonyl chloride using Method G.

¹H NMR (d₆-DMSO) δ=10.88 (s, 1H), 8.37 (t, J=6.0 Hz, 1H), 8.24 (d, J=8.1Hz, 1H), 8.06 (d, J=8.1 Hz, 1H), 8.01 (d, J=8.4 Hz, 1H), 7.89 (d, J=8.4Hz, 1H), 7.60 (t, J=7.8 Hz, 1H), 7.53 (t, J=7.8 Hz, 1H), 7.45 (d, J=8.4Hz, 1H), 7.34-7.07 (m, 8H), 6.53 (d, J=7.8 Hz, 1H), 5.03 (dd, J=4.8, 8.7Hz, 1H), 4.33-4.26 (m, 1H), 4.16-4.09 (m, 1H), 2.44-2.21 (m, 2H).

Example 170 Preparation of 2-[2-(R.S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(4-aminobenzyl)acetamide

The title compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(4-nitrobenzyl)acetamideusing Method K.

¹H NMR (d₆-DMSO) δ=10.51 (s, 1H), 8.50 (t, J=5.7 Hz, 1H), 7.46-7.26 (m,7H), 7.10 (t, J=7.8 Hz, 1H), 4.94 (dd, J=4.8, 9.3 Hz, 1H), 4.33 (dd,J=5.4, 15.3 Hz, 1H), 4.15 (dd, J=5.4, 15.3 Hz, 1H), 3.56 (bs, 2H), 2.36(dd, 1H, J=5.3, 15.3 Hz), 2.28-2.20 (m, 4H), 1.97 (s, 3H).

Example 171 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-methoxy]-N-methylacetamide

The title compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-di-methylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and N,O-dimethylhydroxylamine using Method I.

¹H NMR (d₆-DMSO) δ=10.56 (s, 1H), 7.49-7.40 (m, 3H), 7.28 (t, J=7.8 Hz,1H), 7.09 (t, J=7.8 Hz, 1H), 6.84 (d, J=7.8, 1H), 4.90 (dd, J=5.4, 8.1Hz, 1H), 3.45 (s, 3H), 3.04 (s, 3H), 2.55-2.44 (m, 2H), 2.23 (s, 3H),2.02 (s, 3H).

Example 172 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(4-carboxybenzyl)acetamide

The title compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-di-methylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and methyl 4-(aminomethyl)benzoate using Method I. The resultingproduct was then hydrolyzed using Method C.

¹H NMR (d₆-DMSO) δ=10.51 (s, 1H), 8.55 (t, J=5.8 Hz, 2H), 7.93 (d, J=8.4Hz, 1H), 7.46-7.40 (m, 5H), 7.34 (t, J=8.4 Hz, 1H), 7.11 (t, J=8.4 Hz,1H), 6.82 (d, J=8.4, 1H), 4.94 (dd, J=4.2, 9.9 Hz, 1H), 4.44 (dd, J=6.0,16.5 Hz, 1H), 2.40 (dd, J=6.0, 16.5 Hz, 1H), 2.30-2.22 (m, 4H), 1.99 (s,3H).

Example 173 Preparation of2-[2-(R,S)-1-(2-chlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-benzylacetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-benzylacetamidecondensed to 2-chlorophenyl-sulfonyl chloride using Method G.

¹H NMR (d₆-DMSO) δ=10.54 (s, 1H), 8.34 (t, J=6.0 Hz, 1H), 7.83 (dd,J=2.2, 7.9 Hz, 1H), 7.43-7.49 (m, 2H), 7.15-7.33 (m, 6H), 7.01 (dt,J=1.5, 7.9 Hz, 1H), 6.84 (dd, J=1.5, 7.9 Hz, 1H), 5.08 (dd, J=5.8, 9.0Hz, 1H), 4.28 (dd, J=6.0, 15.0 Hz, 1H), 4.16 (dd, J=6.0, 15.0 Hz, 1H),2.41 (dd, J=5.8, 15.0 Hz, 1H), 2.33 (dd, J=9.0, 15.0 Hz, 1H).

Example 174 Preparation of2-[2-(R,S)-1-(3-chlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-benzylacetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-benzylacetamidecondensed with 3-chlorophenyl-sulfonyl chloride using Method G.

¹H NMR (d₆-DMSO) δ=10.36 (s, 1H), 8.35 (t, J=5.7 Hz, 1H), 7.76 (dd,J=2.2, 7.9 Hz, 1H), 7.52 (t, J=8.3 Hz, 1H), 7.46 (dd, J=1.4, 7.9 Hz,1H), 7.20-7.34 (m, 8H), 7.12 (dt, J=1.4, 7.9 Hz, 1H), 6.80 (dd, J=2.2,7.9 Hz, 1H), 5.01 (dd, J=5.8, 9.0 Hz, 1H), 4.34 (dd, J=6.0, 15.0 Hz,1H), 4.16 (dd, J=6.0, 15.0 Hz, 1H), 2.38 (dd, J=5.8, 15.0 Hz, 1H), 2.26(dd, J=9.0, 15.0 Hz, 1H).

Example 175 Preparation of2-[2-(R,S)-1-(3,4-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-benzylacetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-benzylacetamidecondensed with 3,4-dichloro-phenylsulfonyl chloride using Method G.

¹H NMR (d₆-DMSO) δ=10.42 (s, 1H), 8.36 (t, J=5.8 Hz, 1H), 7.78 (d, J=7.9Hz, 1H), 7.45 (d, J=7.9 Hz, 1H), 7.24-7.37 (m, 8H), 7.13 (d, J=7.9 Hz,1H), 6.82 (d, J=7.9 Hz, 1H), 5.00 (dd, J=5.8, 9.0 Hz, 1H), 4.34 (dd,J=6.0, 15.0 Hz, 1H), 4.15 (dd, J=6.0, 15.0 Hz, 1H), 2.39 (dd, J=5.8,14.9 Hz, 1H), 2.26 (dd, J=9.0, 14.9 Hz, 1H).

Example 176 Preparation of2-[2-(R,S)-1-(2,4,6-trichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-benzylacetamide

The title compound was from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]-N-benzylacetamidecondensed to 2,4,6-trichlorophenylsulfonyl chloride using Method G.

¹H NMR (d₆-DMSO) δ=10.72 (s, 1H), 8.38 (t, J=5.8 Hz, 1H), 7.86 (s, 2H),7.51 (d, J=7.9 Hz, 1H), 7.20-7.31 (m, 6H), 7.04 (t, J=7.9 Hz, 1H), 6.90(d, J=7.9 Hz, 1H), 5.07 (dd, J=5.8, 9.0 Hz, 1H), 4.24 (dd, J=6.0, 15.0Hz, 1H), 4.15 (dd, J=6.0, 15.0 Hz, 1H), 2.30-2.49 (m, 2H).

Example 177 Preparation of2-[2-(R,S)-1-(2,3-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-phenethylacetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetra-hydroquinoxalin-2-yl]acetic acid andphenethyl amine using Method D followed by condensation with2,3-dichlorophenylsulfonyl chloride using Method G.

MS (ES): m/e 541 (M⁺+Na);

HPLC (CH₃CN—H₂O-0.1% TFA) (long column): R_(t)=28.11 min.

Example 178 Preparation of2-[2-(R,S)-1-(2,4,5-trichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-benzylacetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-benzylacetamidecondensed to 2,4,5-trichlorophenylsulfonyl chloride using Method G.

¹H NMR (d₆-DMSO) δ=10.74 (s, 1H), 8.46 (t, J=5.4 Hz, 1H), 8.15 (s, 3H),7.89 (s, 3H), 7.53 (d, J=7.8 Hz, 1H), 7.39-7.27 (m, 6H), 7.13 (dt,J=1.2, 7.8 Hz, 1H), 6.91 (dd, J=1.2, 7.8, 1H), 5.05 (dd, J=4.2, 9.3 Hz,1H), 4.35 (dd, J=6.0, 15.0 Hz, 1H), 4.19 (dd, J=6.0, 15.0 Hz, 1H), 2.46(dd, J=4.2, 14.7 Hz, 1H), 2.35 (dd, J=9.3, 14.7 Hz, 1H).

Example 179 Preparation of2-[2-(R,S)-1-(3,5-bis(trifluoromethyl)benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-benzylacetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-benzylacetamidecondensed to 3,5-di(trifluoro-methyl)phenylsulfonyl chloride usingMethod G.

¹H NMR (d₆-DMSO) δ=10.37 (s, 1H), 8.59 (s, 1H), 8.42 (t, J=5.8 Hz, 1H),7.67 (s, 2H), 7.49 (d, J=8.7 Hz, 1H), 7.15-7.35 (m, 8H), 5.02 (dd,J=5.4, 11.9 Hz, 1H), 4.33 (dd, J=6.0, 15.0 Hz, 1H), 4.15 (dd, J=6.0,15.0 Hz, 1H), 2.25-2.44 (m, 2H).

Example 180 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(4-phenylbut-1-yl)acetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]acetic acid andphenylbutylamine using Method D followed by reaction with2,5-dimethyl-4-chlorophenylsulfonyl chloride using Method G.

¹H NMR (d₆-DMSO) δ=10.41 (s, 1H), 7.81 (t, J=5.8 Hz, 1H), 7.46 (s, 1H),7.40 (s, 1H), 7.35 (d, J=7.9 Hz, 1H), 7.24-7.29 (m, 3H), 7.14-7.20 (m,3H), 7.04 (t, J=7.9 Hz, 1H), 6.83 (d, J=7.9 Hz, 1H), 4.86 (dd, J=5.4,10.0 Hz, 1H), 2.92-3.07 (m, 2H), 2.56 (t, J=7.2 Hz, 2H), 2.10-2.77 (m,4H), 2.04 (s, 3H), 1.50-1.1.58 (m, 2H), 1.32-1.39 (m, 2H).

Example 181 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(piperidin-N-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]acetic acid and1-aminoethylpiperidine using Method D followed by reaction with2,5-dimethyl-4-chlorophenylsulfonyl chloride using Method G.

¹H NMR (d₆-DMSO) δ=10.48 (s, 1H), 9.90 (bs, 1H), 8.34 (t, J=5.7 Hz, 1H),7.42-7.47 (m, 3H), 7.29 (t, J=7.6 Hz, 1H), 7.11 (t, J=7.6 Hz, 1H), 6.84(d, J=7.6 Hz, 1H), 4.91 (dd, J=5.1, 9.0 Hz, 1H), 3.41-3.44 (m, 4H),2.87-3.04 (m, 3H), 2.18-2.36 (m, 5H), 2.01 (s, 3H), 1.68-1.1.78 (m, 4H),1.03-1.07 (m, 3H).

Example 182 Preparation of2-[2-(R,S)-1-(2,3-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-isopropylacetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]acetic acid andisopropylamine using Method D; this was then reacted with2,3-dichlorophenylsulfonyl chloride using Method G.

¹H NMR (d₆-DMSO) δ=10.60 (s, 1H), 7.93 (dd, J=1.4, 7.9 Hz, 1H), 7.86 (d,J=1.4, 7.9 Hz, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.47-7.52 (m, 2H), 7.20 (t,J=7.6 Hz, 1H), 7.04 (t, J=7.6 Hz, 1H), 6.87 (d, J=7.6 Hz, 1H), 4.99 (dd,J=5.8, 9.0 Hz, 1H),3.74 (m, 1H), 2.15-2.29 (m, 2H), 1.04 (d, J=6.5 Hz,3H), 0.94 (d, J=6.5 Hz, 3H).

Example 183 Preparation of2-[2-(R,S)-1-(2-methyl-5-nitrobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-benzylacetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-benzylacetamidecondensed to 2-methyl-5-nitrophenyl-sulfonyl chloride using Method G.

MS (ES): m/e 495 (M+H);

HPLC (H₂O—CH₃CN-0.1% TFA) (long column): R_(t)=28.08 min.

Example 184 Preparation of2-[2-(R,S)-1-(2,3-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N,N-diisopropylacetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]acetic acid anddiisopropylamine using Method D followed by reaction with2,3-dichlorophenylsulfonyl chloride using Method G.

¹H NMR (d₆-DMSO) δ=10.65 (s, 1H), 7.93 (dd, J=1.4, 8.3 Hz, 1H), 7.86 (d,J=1.4, 8.3 Hz, 1H), 7.48-7.53 (m, 2H), 7.20 (dt, J=1.4, 7.6 Hz, 1H),7.02 (dt, J=1.4, 7.6 Hz, 1H), 6.88 (dd, J=1.4, 7.6 Hz, 1H), 5.01 (dd,J=4.7, 7.9 Hz, 1H), 3.67-3.73 (m, 1H), 3.46-3.5 (m, 1H), 2.39-2.47 (m,2H), 0.95-1.28 (m, 12H).(25)

Example 185 Preparation of2-[2-(R,S)-1-(2,3-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-2-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]acetic acid and2-aminoethylpyridine using Method D followed by reaction with2,3-dichlorophenylsulfonyl chloride using Method G.

¹H NMR (d₆-DMSO) δ=10.64 (s, 1H), 8.73 (d, J=5.0 Hz, 1H), 8.36 (t, J=7.2Hz, 1H), 8.08 (t, J=5.8 Hz, 1H), 7.94 (dd, J=7.9, 1.4 Hz, 1H, 7.85-7.77(m, 3H), 7.50 (t, J=7.9 Hz, 1H), 7.43 (d, J=7.9 Hz, 1H), 7.21 (dt,J=7.8, 1.4 Hz, 1H), 7.03 (dt, J=7.8, 1.4 Hz, 1H), 6.87 (dd, J=7.8, 1.4Hz, 1H);

MS (ES): m/e 520 (M+H).

Example 186 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-benzyl-N-methylacetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]acetic acid andN-methylbenzylamine using Method D followed by reaction with2,5-dimethyl-4-chlorophenylsulfonyl chloride using Method G.

¹H NMR (d₆-DMSO) δ=10.49 (s, 0.67H),10.43 (s, 0.33H),7.48-7.19 (m, 8H),7.09-7.00 (m, 2H), 6.85 (d, J=7.6 Hz, 0.67H), 6.77 (d, J=7.6 Hz, 0.33H),5.04-4.99 (m, 1H), 4.64 (d, J=14.4 Hz, 0.67H), 4.46 (d, J=17.0 Hz,0.33H), 4.33 (d, J=14.4 Hz, 0.67H), 4.22 (d, J=17.0 Hz, 0.33H), 2.77 (s,1H), 2.67 (s, 2H), 2.62-2.48(m, 2H), 2.23 (s, 3H), 2.05-2.04 (m, 3H);

MS (ES): m/e 513 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (long column): R_(t)=31.08 min.

Example 187 (Intermediate Compound) Preparation of2-[2-(R,S)-1-(4-Chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid

The title compound was synthesized through multi-step procedures: firststarting from 1,2-phenylenediamine and maleimide using Methods F then E;then reacting with 2,5-dimethyl-4-chlorophenylsulfonyl chloride usingMethod G to lead to the title compound.

¹H NMR (d₆-DMSO) δ=10.46 (s, 0.67H), 7.52 (s, 1H), 7.30 (dt, J=1.2, 7.5Hz, 1H), 7.11 (dt, J=1.2, 7.5 Hz, 1H), 6.85 (dd, J=1.2, 7.5 Hz, 1H),4.96 (dd, J=4.8, 9.3 Hz, 1H), 2.26 (s, 3H), 2.19 (dd, J=4.8, 15.6 Hz,1H), 2.08-2.00 (m, 4H);

¹³C NMR (d₆-DMSO) δ=172.31, 167.69, 138.93, 137.32, 134.53, 134.58,134.25, 133.20, 132.71, 129.04, 128.72, 123.30, 122.08, 116.42, 45.76,37.99, 19.50, 19.32;

MS (ES): m/e 409 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=4.94 min.

Example 188 (Intermediate Compound) Preparation of2-[2-(R,S)-1-(4-dichloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]methoxyacetic acid

2-[2-(R,S)-1-(4-Chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetra-hydroquinoxalin-2-yl]aceticacid (483 mg, 1.18 mmol) was dissolved in methanol (30 ml). The solutionwas heated under reflux with catalytic amount of conc. H₂SO₄ overnight.The solvent was concentrated to almost dryness and the solid was washedwith water. After drying in the desicator, a white solid was obtained asthe title compound.

¹H NMR (d₆-DMSO) δ=10.61 (s, 1H), 7.52-7.40 (m, 3H), 7.29 (t, J=7.5 Hz,1H), 7.11 (t, J=7.5 Hz, 1H), 6.83 (d, J=7.5 Hz, 1H), 4.79 (dd, J=4.5,9.6 Hz, 1H), 3.56 (s, 3H), 2.63 (dd, J=4.5, 14.7 Hz, 1H), 2.33-2.49 (m,4H), 1.99 (s, 3H);

MS (ES): m/e 446 (M⁺+Na);

HPLC (CH₃CN—H₂O-0.1% TFA) (long column): R_(t)=28.65 min.

Example 189 Preparation of 2-[2-(R.S-1-(2,4,6-trimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-cyclohexylmethylacetamide

A mixture of 2-[2-(R,S)-1-(2,4,6,trimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-benzylacetamide(100 mg, 0.21 mmol), PtO₂ (20 mg) in ethanol (25 mL) and glacial aceticacid (1.5 mL) was hydrogenated under a hydrogen balloon overnight. Thereaction mixture was filtered through celite and rinsed with ethanol.The solvent was then evaporated under reduced pressure and the solid waswashed with water several times. The title compound was obtained as awhite solid after drying in the desicator.

¹H NMR (d₆-DMSO) δ=10.61 (s, 1H), 7.72 (t, J=4.7 Hz, 1H), 7.26-7.22 (m,1H), 7.03-6.93 (m, 5H), 4.77 (dd, J=4.3, 9.0 Hz, 1H), 2.86 (q, J=6.5,12.6 Hz, 1H), 2.70 (q, J=6.5, 12.6 Hz, 1H), 2.33 (s, 6H), 2.27 (m, 4H),2.13 (dd, J=9.0, 14.1 Hz, 1H), 1.62-0.75 (m, 1H);

MS (ES): m/e 506 (M⁺+Na);

HPLC (CH₃CN—H₂O-0.1% TFA) (long column): R_(t)=31.22 min.

Example 190 (Intermediate Compound) Preparation of2-[2-(R,S)-3-Oxo-1-(2,4,6-trimethylbenzenesulfonyl)-1,2,3,4-tetrahydroquinoxalin-2-yl]-aceticacid

Preparation of the title material followed the general proceduredescribed in Method G with2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]acetic acid and2,4,6-trimethylbenzenesulfonyl chloride.

¹H NMR (d₆-DMSO) δ=12.55 (s, 1H), 10.68 (s, 1H), 7.28 (dt, J=1.6, 8.4Hz, 1H), 7.10-7.07 (m, 3H), 7.01 (dt, J=1.6, 8.4 Hz, 1H), 6.95 (dd,J=1.6, 8.4 Hz, 1H), 4.66 (dd, J=4.4, 10.4 Hz, 1H), 2.50-2.45 (m, 1H),2.36 (s, 6H), 2.28 (s, 3H), 2.13 (dd, J=10.4, 15.2 Hz, 1H);

HPLC (CH₃CN—H₂O-0.1% TFA) (long column): R_(t)=23.22 min.

Example 191 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(piperidin-2-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-2-yl)eth-1-yl]acetamideusing Method L (Step A).

¹H NMR (d₆-DMSO HCl salt) δ=10.49 (s, 1H), 8.26-8.20 (m, 1H), 7.46-7.40(m, 3H), 7.30 (t, J=7.5 Hz, 1H), 7.12 (t, J=7.5 Hz, 1H), 6.82 (d, J=7.5Hz, 1H), 4.90-4.87 (m, 1H), 3.29-3.25 (m, 2H), 3.06-2.88 (m, 3H),2.38-2.10 (m, 5H), 1.95 (s, 3H), 1.90-1.35 (m, 8H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=3.62, 3.74 min.(provides a pair of diastereomers).

Example 192 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethlbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(piperidin-2-ylmethyl)acetamide

The title compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(pyrid-2-ylmethyl)acetamideusing Method L (Step A).

¹H NMR (d₆-DMSO HCl salt) δ=10.55 (s, 1H), 8.30-8.26 (m, 1H), 7.48-7.41(m, 3H), 7.30 (t, J=7.5 Hz, 1H), 7.12 (t, J=7.5 Hz, 1H), 6.84 (d, J=7.5Hz, 1H), 4.92 (dd, J=5.4, 9.3 Hz, 1H), 3.29-3.11 (m, 3H), 3.08-2.91 (m,1H), 2.88-2.72 (m, 1H), 2.36 (dd, J=5.4, 14.4 Hz, 1H), 2.25-2.18 (m,4H), 1.99 (s, 3H), 1.83-1.31 (m, 6H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=3.88 (broad) min.

Example 193 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(2-pyrid-3-yleth-1-yl)acetamide

The title compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-di-methylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and 3-aminoethylpyridine using Method I.

¹H NMR (d₆-DMSO) δ=10.47 (s, 1H), 8.42-8.41 (m, 2H), 8.00 (t, J=4.8 Hz,1H), 7.61 (d, J=7.5 HZ, 1H), 7.47-7.24 (m, 5H), 7.08 (t, J=7.5 Hz, 1H),6.81 (d, J=7.5 Hz, 1H), 4.86 (dd, J=4.8, 9.3 Hz, 1H), 3.32-3.12 (m, 2H),2.71-2.64 (m, 2H), 2.25-2.09 (m, 5H), 1.99 (s, 3H);

¹³C NMR (d₆-DMSO) d 167.62, 166.95, 150.54, 148.08, 139.14, 137.42,136.88, 135.57, 134.61, 134.33, 134.09, 133.30, 132.75, 129.12, 128.87,124.05, 123.45, 121.71, 116.45, 56.34, 36.67, 32.37, 19.40, 19.34.

Example 194 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[(N-methyl)pyrrolidin-2-yl]eth-1-yl}acetamide

The title compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and 2-(1-methyl-pyrrolidin-2-yl)-ethylamine using Method I.

¹H NMR (d₆-DMSO) δ=10.46 (s, 1H), 7.88-7.85 (m, 1H), 7.47-7.38 (m, 3H),7.28 (t, J=7.8 Hz, 1H), 7.10 (t, J=7.8 Hz, 1H), 6.82 (d, J=7.8 Hz, 1H),4.86 (dd, J=4.8, 9.3 Hz, 1H), 3.11-3.01 (m, 1H), 2.99-2.88-(m, 2H),2.22-2.2.12 (m, 8H), 2.09-1.98 (m, 5H), 1.91-1.80 (m, 1H), 1.71-1.55 (m,3H), 1.38-1.15 (m, 2H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=3.43 min. (broad).

Example 195 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(piperidin-3-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(2-pyrid-3-yleth-1-yl)acetamideusing Method L (Step A).

¹H NMR (d₆-DMSO HCl salt) δ=10.50 (d, J=7.2 Hz, 1H), 7.98-7.90 (m, 1H),7.46-7.40 (m, 3H), 7.28 (t, J=7.8 Hz, 1H), 7.11 (t, J=7.8. Hz, 1H), 6.85(d, J=7.8 Hz, 1H), 4.86 (dd, J=5.7, 9.3 Hz, 1H), 3.20-3.11 (m, 2H),3.06-2.92 (m, 2H), 2.78-2.68 (m, 1H), 2.31-2.01 (m, 5H), 2.00 (s, 3H),1.78-1.08 (m, 8H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=3.43 min.

Example 196 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[3-(dimethylamino)prop-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-di-methylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and N,N-dimethylethylenediamine using Method I.

¹H NMR (d₆-DMSO) δ=10.46 (s, 1H), 7.87 (t, J=5.4 Hz, 1H), 7.46-7.39 (m,3H), 7.28(t, J=7.8 Hz, 1H), 7.10 (t, J=7.8 Hz, 1H), 6.82 (d, J=7.8 Hz,1H), 4.86 (dd, J=5.1, 9.3 Hz, 1H), 3.08-2.88 (m, 2H), 2.30-2.09 (m, 1H),2.01 (s, 3H), 1.51-1.44 (m, 2H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=3.29 min.

Example 197 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(N-methylpiperidin-2-yl)]acetamide

The title compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-2-yl)eth-1-yl]acetamideby Method J and Method K.

¹H NMR (d₆-DMSO) δ=10.46 (s, 1H), 7.86-7.80 (m, 1H), 7.47-7.39 (m, 3H),7.28 (t, J=7.5 Hz, 1H), 7.10 (t, J=7.5 Hz, 1H), 6.82 (d, J=7.5 Hz, 1H),4.88-4.83 (m, 1H), 3.11-2.89 (m, 2H), 2.73-2.69 (m, 1H), 2.26-2.20 (m,4H), 2.15-2.08 (m, 4H), 2.02 (s, 3H), 1.96-1.83 (m, 2H), 1.65-1.15 (m,8H);

MS (ES): m/e 534 (M+H).

Example 198 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(N-methylpiperidin-3-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(2-pyrid-3-yleth-1-yl)acetamideby Method J and Method K.

¹H NMR (d₆-DMSO) δ=10.46 (s, 1H), 7.84 (t, J=5.4 Hz, 1H), 7.47-7.39 (m,3H), 7.27 (t, J=7.5 Hz, 1H), 7.08 (t, J=7.5 Hz, 1H), 6.82 (d, J=7.5 Hz,1H), 4.84 (dd, J=6.0, 9.0 Hz, 1H), 3.05-2.88 (m, 2H), 2.64-2.61 (m, 2H),2.28-2.21 (m, 4H), 2.17-2.10 (m, 4H), 2.02 (s, 3H), 1.79-0.75 (m, 8H);

MS (ES): m/e: 534 (M+H).

Example 199 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[(N-methylpiperidin-2-yl)methyl]acetamide

The title compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(pyrid-2-ylmethyl)acetamideby Method J and Method K.

¹H NMR (d₆-DMSO) δ=10.46 (s, 1H), 7.74-7.68 (m, 1H), 7.45-7.36 (m, 3H),7.28 (t, J=7.5 Hz, 1H), 7.12 (t, J=7.5 Hz, 1H), 6.82 (d, J=7.5 Hz, 1H),4.86 (dd, J=5.7, 8.4 Hz, 1H), 3.32-3.29 (m, 1H), 3.04-2.79 (m, 2H),2.72-2.68 (m, 1H), 2.42-1.91 (m, 13H), 1.81-1.15 (m, 8H).

Example 200 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-cyanomethylacetamide

The title compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-di-methylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and aminoacetonitrile using Method I.

¹H NMR (d₆-DMSO) δ=10.52 (s, 1H), 8.66 (t, J=5.4 Hz, 2H), 7.48-7.39 (m,3H), 7.29 (t, J=7.5 Hz, 1H), 7.11 (t, J=7.5 Hz, 1H), 6.84 (d, J=7.5 Hz,1H), 4.85 (dd, J=4.8, 9.3 Hz, 1H), 4.11-4.09 (m, 2H), 2.28 (dd, J=4.8,14.7 Hz, 1H), 2.27-2.19 (m, 4H), 2.00 (s, 3H);

¹³C NMR (d₆-DMSO) δ 168.42, 166.57, 139.23, 137.43, 134.67, 134.19,134.02, 133.34, 132.75, 129.26, 128.80, 123.58, 121.54, 117.99, 116.54,56.07, 36.19, 27.45, 19.40, 19.34;);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=4.11 min.

Example 201 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-aminoacetamide

To the solution of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]aceticacid (460 mg, 1.1 mmol) in methanol (20 ml) was added hydrazine hydrate(0.16 ml, 3.3 mmol). The resulting solution was stirred at roomtemperature overnight. Most of the solvent was removed under reducedpressure and the final small volume solution was place into arefrigerator overnight. The solid was isolated through filtration andwashed with small amount of water to give the title compound.

¹H NMR (d₆-DMSO) δ=8.96 (s, 1H), 7.45-7.39 (m, 3H), 7.28 (t, J=7.5 Hz,1H), 7.11 (t, J=7.5 Hz, 1H), 6.81 (d, J=7.5 Hz, 1H), 4.87 (dd, J=5.7,9.0 Hz, 1H), 2.23-2.10 (m, 5H), 1.99 (s, 3H);

MS (ES): m/e 423 (M+H).

Example 202 Preparation of 2-[2-(R,S)1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-methylcarboxamideacetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-cyanomethylacetamide(500 mg, 1.12 mmol) was suspended in conc. HCl (10 mL) and was stirredat room temperature for 24 hours. The solid was then isolated throughfiltration and washed with water a few times to give a white solid asthe title compound.

¹H NMR (d₆-DMSO) δ=10.50 (s, 1H), 8.18 (t, J=5.4 Hz, 2H), 7.48-7.39 (m,3H), 7.28 (dt, J=1.3, 7.7 Hz, 1H), 7.16-7.06 (m, 2H), 6.83 (dd, J=1.3,7.7 Hz, 1H), 4.87 (dd, J=5.9, 8.4 Hz, 1H), 3.57-3.55 (m, 2H), 2.38-2.26(m, 2H), 2.23 (s, 3H), 2.01 (s, 3H);

MS (ES): m/e 487 (M⁺+Na);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=3.37 min.

Example 203 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-phenyleth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-di-methylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and (R)-1-phenylethylamine using Method I.

¹H NMR (d₆-DMSO) δ=10.52 (s, 1H), 8.39-8.35 (m, 1H), 7.51-6.98 (m, 10H),6.88 (d, J=7.8 Hz, 1H), 4.96-4.93 (m, 2H), 2.48-2.20 (m, 5H), 2.07 (s,1.5H), 1.99 (s, 1.5H), 1.35 (d, J=7.4 HZ, 1.5H), 1.31 (d, J=7.4 Hz,1.5H);

MS: m/z (EI+) 533 (M⁺+Na);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=5.31, 5.36 min (provideda pair of diasteromers).

Example 204 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(S)-phenyleth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-di-methylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and (S)-1-phenylethylamine using Method I.

¹H NMR (d₆-DMSO) δ=10.52 (s, 1H), 8.39-8.35 (m, 1H), 7.51-6.98 (m, 10H),6.88 (d, J=7.8 Hz, 1H), 4.96-4.93 (m, 2H), 2.48-2.20 (m, 5H), 2.07 (s,1.5H), 1.99 (s, 1.5H), 1.35 (d, J=7.4 HZ, 1.5H), 1.31 (d, J=7.4 Hz,1.5H);

MS: m/z (EI+) 535 (M⁺+Na);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=5.31, 5.36 min.

Example 205 Preparation of2-[2-(S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamide

The title compound was synthesized from 1,2-fluoronitrobenzene andL-aspartic acid using Methods A, B, and C; the resulting product wasreacted with 2,5-dimethyl-4-chlorophenylsulfonyl chloride using MethodH; reaction with 2-aminoethylpyridine using Method I led to the titlecompound.

¹H NMR (d₆-DMSO, TFA salt) δ=10.52 (s, 1H), 8.82 (d, J=6.6 Hz, 2H), 8.09(t, J=5.4 Hz, 1H), 7.85 (d, J=6.6 Hz, 2H), 7.48 (s, 1H), 7.47 (s, 1H),7.39-7.30 (m, 2H), 7.14 (dt, J=1.2, 7.5 Hz, 1H), 6.86 (dd, J=1.2, 7.5Hz, 1H), 4.88 (dd, J=4.8, 9.3 Hz, 1H), 3.49-3.38 (m, 2H), 3.00-2.91 (m,2H), 2.30-2.24 (m, 4H), 2.15 (dd, J=9.6, 14.4 Hz, 1H), 2.01 (s, 3H);

MS (ES): m/e: 514 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=3.45 min.

Example 206 Preparation of2-[2-(R)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamide

The title compound was synthesized from 1,2-fluoronitrobenzene andD-aspartic acid using Methods A, B, and C; reaction with2,5-dimethyl-4-chlorophenylsulfonyl chloride using Method H followed byreaction with 2-aminoethylpyridine using Method I led to the titlecompound.

¹H NMR (d₆-DMSO HCl salt) δ=10.48 (s, 1H), 8.82 (d, J=6.6 Hz, 2H), 8.06(t, J=5.4 Hz, 1H), 7.90 (d, J=6.6 Hz, 2H), 7.42 (s, 1H), 7.41 (s, 1H),7.34-7.25 (m, 2H), 7.09 (t, J=7.5 Hz, 1H), 6.82 (d, J=7.5 Hz, 1H), 4.83(dd, J=5.1, 9.0 Hz, 1H), 3.67-3.60 (m, 2H), 3.02-2.91 (m, 2H), 2.25-2.19(m, 4H), 2.10 (dd, J=9.0, 14.1 Hz, 1H), 1.97 (s, 3H);

MS (ES): m/e: 514 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=3.34 min.

Example 207 Preparation of2-[2-(R)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(N-methylpiperidin-4-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamideusing Methods J and K.

MS (ES): m/e 534 (M+H), 556 (M+Na).

Example 208 Preparation of2-[2-(S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(N-methylpiperidin-4-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamideusing Methods J and K.

MS (ES): m/e 534 (M+H), 556 (M+Na);

HPLC (acetonitrile-water-0.1% TFA) R_(t)=4.39 min

Example 209 Preparation ofN-[2-(4-Amino-phenyl)-ethyl]-2-[1-(4-chloro-2,5-dimethyl-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-acetamide

The title compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-di-methylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and 4-aminoethylaniline using Method I.

¹H NMR (d₆-DMSO) δ=10.46 (s, 1H), 7.90 (t, J=5.4 Hz, 1H), 7.48-7.35 (m,3H), 7.27 (dt, J=1.8, 7.8 Hz, 1H), 7.20-7.17 (m, 1H), 7.09 (dt, J=1.8,7.8 Hz, 1H), 6.83-6.76 (m, 3H), 6.48 (d, J=9.3 Hz, 2H), 4.89-4.84 (m,2H), 3.16-2.90 (m, 2H), 2.49-2.42 (m, 2H), 2.25-2.15 (m, 5H), 2.02 (s,3H);

MS (ES): m/e: 527 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=3.56 min.

Example 210 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(pyrid-4-ylmethyl)acetamide

The title compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-di-methylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and 4-aminomethylpyridine using Method I.

¹H NMR (d₆-DMSO) δ=10.56 (s, 1H), 8.59-8.53 (m, 3H), 7.51-7.47 (m, 3H),7.37-7.30 (m, 3H), 7.17 (t, J=7.8 Hz, 1H), 6.88 (d, J=7.8 Hz, 1H), 4.98(dd, J=5.0, 9.9 Hz, 1H), 4.38 (dd, J=6.0, 16.5 Hz, 1H), 4.23 (dd, J=5.4,16.5 Hz, 1H), 2.46 (dd, J=5.0, 14.1 Hz, 1H), 2.36-2.27 (m, 4H), 2.04 (s,3H).

Example 211 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-cyanophenyl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-di-methylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and 4-aminoethylbenzonitrile using Method I.

¹H NMR (CD₃OD) δ=8.11 (bs, 1H), 7.68 (d, J=8.1 Hz, 2H), 7.51-7.43 (m,4H), 7.30-7.24 (m, 2H), 7.11 (dt, J=1.2, 8.1 Hz, 1H), 6.79 (dd, J=1.2,8.1 Hz, 1H), 5.09 (dd, J=5.1, 9.9 Hz, 1H), 3.51-3.44 (m, 1H), 3.39-3.31(m, 1H), 2.92-2.82 (m, 2H), 2.37 (dd, J=4.8, 14.1 Hz, 1H), 2.27-2.19 (m,4H), 2.04 (s, 3H);

MS (ES): m/e 537 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=5.73 min.

Example 212 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[(pyrid-3-yl)methyl]acetamide

The title compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-di-methylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and 3-aminomethylpyridine using Method I.

¹H NMR (d₆-DMSO) δ=10.49 (s, 1H), 8.49-8.44 (m, 3H), 7.66-7.64 (m, 1H),7.66-7.25 (m, 5H), 7.10 (t, J=8.1 Hz, 1H), 6.82 (d, J=8.1 Hz, 1H), 4.91(dd, J=5.1, 9.6 Hz, 1H), 4.32 (dd, J=5.7, 15.6 Hz, 1H), 4.19 (dd, J=5.1,14.1 Hz, 1H), 2.38 (dd, J=5.1, 14.1 Hz, 1H), 2.34-2.20 (m, 4H), 1.99 (s,3H).

Example 213 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-4-t-butoxy-carbonylmethyl-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(t-butoxycarbonylmethyl)piperidin-4-yl]eth-1-yl}acetamide

To a solution of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(piperidin-4-yl)eth-1-yl]acetamide(383 mg, 0.69 mmol) in DMF (10 ml) was added potassium carbonate (286.1mg, 2.1 mmol) and t-butyl bromoacetate (161.5 mg, 0.83 mmol). Theresulting mixture was stirred at room temperature overnight. The solidwas removed through filtration and the filtrate was concentrated underreduced pressure. Column chromatography in silica gel afforded a whitesolid as the title compound.

¹H NMR (CDCl₃) δ=7.64 (dd, J=1.8, 8.4 Hz, 1H), 7.49 (s, 1H), 7.31 (dt,J=1.8, 8.4 Hz, 1H), 7.18 (dt, J=1.8, 8.4 Hz, 1H), 7.11 (s, 1H), 6.55 (d,J=8.1 Hz, 1H), 6.04 (t, J=5.4 Hz, 1H), 5.08 (t, J=5.4 Hz, 1H), 4.44 (d,J=17.0 Hz, 1H), 3.38 (d, J=17.0 Hz, 1H), 3.28-3.14 (m, 2H), 3.07 (s,2H), 2.93-2.85 (m, 2H), 2.39-2.33 (m, 2H), 2.26 (s, 3H), 2.15-2.07 (m,2H), 2.02 (s, 3H), 1.68-1.28 (m, 25H);

¹³C NMR (CDCl₃) d 164.83, 161.98, 161.76, 160.59, 134.53, 131.70,129.60, 129.06, 128.32, 127.62, 127.27, 124.32, 123.80, 119.14, 117.96,109.51, 78.10, 75.67, 55.21, 50.87, 48.26, 38.50, 32.20, 32.04, 30.61,27.64, 26.72, 22.86, 22.67, 14.57, 13.99;

MS (ES): m/e: 747 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=5.40 min.

Example 214 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[1-(t-butoxycarbonylmethyl)piperidin-4-yl]eth-1-yl}acetamide

To a solution of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(piperidin-4-yl)eth-1-yl]acetamide(383 mg, 0.69 mmol) in DMF (10 ml) was added potassium carbonate (286.1mg, 2.1 mmol) and t-butyl bromoacetate (161.5 mg, 0.83 mmol). Theresulting mixture was stirred at room temperature overnight. The solidwas removed through filtration and the filtrate was concentrated underreduced pressure. Column chromatography in silica gel afforded a whitesolid as the title compound.

¹H NMR (CDCl₃) δ=8.64 (S, 1H), 7.63 (dd, J=1.4, 8.3 Hz, 1H), 7.53 (s,1H), 7.28-7.23 (m, 1H), 7.15-7.10 (m, 2H), 6.78 (dd, J=1.3, 8.1 Hz, 1H),6.10 (t, J=5.4 Hz, 1H), 5.02 (dd, J=4.4, 10.4 Hz, 1H), 3.30-3.21 (m,2H), 3.10 (s, 2H), 2.95-2.92 (m, 2H), 2.51 (dd, J=4.6, 15.3 Hz, 1H),2.34 (dd, J=10.0, 15.3 Hz, 1H), 2.24 (s, 3H), 2.16-2.01 (m, 2H), 1.98(s, 3H), 1.70-1.30 (m, 16H);

¹³C NMR (CDCl₃) d 169.75, 167.05, 166.89, 139.65, 136.60, 134.54,133.34, 132.87, 132.21, 131.87, 128.59, 128.25, 124.03, 121.46, 115.94,80.77, 60.26, 55.88, 53.31, 37.31, 36.86, 35.76, 32.66, 31.86, 31.80,28.01, 19.64, 19.18;

MS (ES): m/e: 633 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=4.23 min.

Example 215 Preparation of2-[2-(R)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(2-piperidin-4-yleth-1-yl)acetamide

The title compound was synthesized from2-[2-(R)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamideusing Method K.

¹H NMR (d₆-DMSO HCl salt) δ=10.53 (s, 1H), 7.96 (t, J=5.4 Hz, 1H),7.48-7.43 (m, 3H), 7.34 (t, J=7.5 Hz, 1H), 7.17 (t, J=7.5 Hz, 1H), 6.87(d, J=7.5 Hz, 1H), 4.92 (dd, J=4.5, 9.9 Hz, 1H), 3.31-3.18 (m, 3H),3.02-2.85 (m, 3H), 2.33-2.11 (m, 5H), 2.01 (s, 3H), 1.67-1.27 (m, 7H);

MS (ES): m/e 519 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=3.31 min.

Example 216 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(pyrazin-2-ylmethyl)acetamide

The title compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-di-methylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and 3-aminomethylpyrazine using Method I.

¹H NMR (d₆-DMSO) δ=10.50 (s, 1H), 8.62 (t, J=5.4 Hz, 1H), 8.60-8.53 (m,3H), 7.47-7.39 (m, 3H), 7.26 (t, J=7.8 Hz, 1H), 7.09 (t, J=7.8 Hz, 1H),6.83 (d, J=7.8 Hz, 1H), 4.90 (dd, J=5.3, 8.9 Hz, 1H), 4.40-4.32 (m, 2H),2.38 (dd, J=5.3, 13.9 Hz, 1H), 2.29-2.22 (m, 4H), 1.99 (s, 3H);

¹³C NMR (d₆-DMSO) d 167.74, 166.45, 166.36, 154.15, 144.09, 143.52,138.82, 137.06, 134.30, 133.94, 133.74, 133.60, 132.97, 132.40, 128.87,128.45, 123.20, 121.36, 116.21, 116.15, 56.16, 42.81, 36.52, 19.26,19.22;

MS: m/z (EI+) 500 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=4.40 min.

Example 217 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[(2-aminopyrid-4-yl)methyl]acetamide

The title compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-di-methylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and 2-amino-5-aminomethylpyridine (D. Feng, J. Med. Chem.,40(23):3726-3733 (1997)) using Method I.

¹H NMR (d₆-DMSO) δ=10.54 (s, 1H), 8.47 (t, J=5.4 Hz, 1H), 7.82 (d, J=2.4Hz, 1H), 7.70 (dd, J=2.1, 9.0 Hz, 1H), 7.50-7.40 (m, 3H), 7.32 (dt,J=1.5, 7.8 Hz, 1H), 7.14 (dt, J=1.2, 7.8 Hz, 1H), 6.88-6.84 (m, 2H),4.94 (dd, J=4.8, 9.3 Hz, 1H), 4.19 (dd, J=6.0, 15.0 Hz, 1H), 4.08 (dd,J=6.0, 15.0 Hz, 1H), 2.39 (dd, J=4.8, 14.4 Hz, 1H), 2.27-2.20 (m, 4H),2.03 (s, 3H);

MS (ES): m/e 514 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=3.28 min.

Example 218 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[4-(aminoethyleneamidino)phenyl]eth-1-yl}acetamide

The title compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-cyanophenyl)eth-1-yl]acetamideand ethylenediamine using Method T.

¹H NMR (d₆-DMSO) δ=10.54 (s, 1H), 9.67 (bs, 1H), 8.15 (t, J=5.4 Hz, 1H),8.03 (bs, 1H), 7.80 (d, J=8.1 Hz, 2H), 7.54-7.44 (m, 5H), 7.34 (t, J=7.8Hz, 1H), 7.16 (t, J=7.8 Hz, 1H), 6.87 (d, J=7.8 Hz, 1H), 5.09 (dd,J=5.1, 9.9 Hz, 1H), 3.51-3.44 (m, 1H), 3.39-3.31 (m, 1H), 2.92-2.82 (m,2H), 2.37 (dd, J=4.8, 14.1 Hz, 1H), 2.27-2.19 (m, 4H), 2.04 (s, 3H);

¹³C NMR (d₆-DMSO) d 167.18, 166.49, 163.93, 158.45, 158.03, 146.08,138.81, 137.00, 134.30, 133.95, 133.72, 132.99, 132.33, 129.40, 128.89,128.68, 128.47, 123.21, 121.38, 116.21, 56.17, 37.14, 36.60, 35.20,19.28, 19.24;

MS (ES): m/e: 597 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column) R_(t)=2.99 min.

Example 219 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[4-(imidazolin-2-yl)phenyl]eth-1-yl}acetamide

The title compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-cyanophenyl)eth-1-yl]acetamideand ethylenediamine using Method T.

¹H NMR (d₆-DMSO) δ=10.47 (s, 1H), 10.43 (d, J=3.1 Hz, 1H), 8.04 (t,J=5.4 Hz, 1H), 7.86 (d, J=8.3 Hz, 2H), 7.51 (s, 1H), 7.48 (s, 1H), 7.44(d, J=8.3 Hz, 2H), 7.36 (dd, J=1.4, 9.0 Hz, 1H). 7.28 (dt, J=1.4, 8.0Hz, 1H), 7.08 (dt, J=1.5, 9.0 Hz, 1H), 6.82 (dd, J=1.5, 8.0 Hz, 1H),5.09 (dd, J=5.1, 9.9 Hz, 1H), 3.51-3.44 (m, 1H), 3.39-3.31 (m, 1H),2.92-2.82 (m, 2H), 2.37 (dd, J=4.8, 14.1 Hz, 1H), 2.27-2.19 (m, 4H),2.04 (s, 3H);

¹³C NMR (d₆-DMSO) δ=167.63, 166.91, 165.57, 147.74, 139.16, 137.38,134.63, 134.31, 134.07, 133.32, 132.70, 130.32, 129.19, 129.05, 128.81,123.50, 121.68, 120.57, 116.50, 56.36, 44.82, 36.68, 35.40, 19.40,19.37;

MS (ES): m/e: 580 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=3.65 min.

Example 220 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(2-aminothiazol-5-ylmethyl)acetamide

The title compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-di-methylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and 2-amino-5-aminomethylthiazole (P. Marshaw, J. Med. Chem.38(6):994-1004 (1995); J. Heterocyclic Chem. 18(2):205 (1981)) usingMethod I.

¹H NMR (d₆-DMSO) δ=10.49 (s, 1H), 8.43 (t, J=5.4 Hz, 1H), 7.45-7.41 (m,3H), 7.29 (dt, J=1.5, 7.7 Hz, 1H), 7.09 (dt, J=1.5, 7.7 Hz, 1H), 7.32(d, J=7.7 Hz, 1H), 6.46 (s, 1H), 4.91 (dd, J=5.6, 9.4 Hz, 1H), 4.12-4.07(m, 2H), 2.37 (dd, J=5.4, 15.1 Hz, 1H), 2.28-2.06 (m, 4H), 1.99 (s, 3H);

MS: m/z (EI+) 520 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column) R_(t)=3.49 min.

Example 221 Preparation of2-[1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-phenethylacetamide

The title compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-di-methylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and 3-phenylethylamine using Method I.

¹H NMR (d₆-DMSO) δ=10.47 (s, 1H), 7.94 (t, J=5.4 Hz, 1H), 7.48-7.408 (m,10H), 6.82 (d, J=7.5 Hz, 1H), 4.92 (dd, J=5.3, 9.2 Hz, 1H), 3.26-3.12(m, 2H), 2.67 (t, J=7.1 Hz, 2H), 2.23-2.11 (m, 5H), 2.02 (s, 3H);

¹³C NMR (d₆-DMSO) d 167.01, 166.74, 139.76, 138.79, 137.09, 134.27,134.00, 132.97, 132.41, 128.96, 128.79, 128.63, 128.51, 126.38, 123.13,121.40, 119.92, 116.15, 56.15, 53.52, 36.72, 35.24, 19.29, 19.23;

MS (ES): m/e: 513 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=6.11 min.

Example 222 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(3-phenylprop-1-yl)acetamide

The title compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-di-methylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and 3-phenylpropylamine using Method I.

¹H NMR (d₆-DMSO) δ=10.49 (s, 1H), 7.98 (t, J=5.4 Hz, 1H), 7.52 (s, 1H),7.46-7.44 (m, 2H), 7.35-7.19 (m, 6H), 7.13 (t, J=7.5 Hz, 1H), 6.88 (d,J=7.5 Hz, 1H), 4.92 (dd, J=5.1, 9.3 Hz, 1H), 3.11-2.94 (m, 2H), 2.60 (t,J=6.9 Hz, 2H), 2.35-2.19 (m, 5H), 2.05 (s, 3H), 1.67 (p, J=6.6 HZ, 2H);

¹³C NMR (d₆-DMSO) d 167.01, 166.53, 142.10, 138.78, 137.04, 134.27,134.01, 132.81, 132.39, 130.11, 128.69, 128.57, 128.48, 126.02, 123.14,121.41, 119.92, 116.15, 56.27, 38.54, 36.73, 32.72, 31.13, 19.29, 19.22;

MS (ES): m/e: 527 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=6.41 min.

Example 223 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-4-methyl-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamide

The title compound was synthesized from N-methyl-1,2-phenylene diamineand oxalacetic acid diethyl ester using Method V.

¹H NMR (d₆-DMSO) δ=8.52-8.50 (m, 2H), 8.04 (t, J=5.4 Hz, 1H), 7.47-7.39(m, 4H), 7.27-7.22 (m, 3H), 7.16 (d, J=8.1 Hz, 1H), 5.03 (dd, J=4.8, 8.7Hz, 1H), 3.32-3.21 (m, 2H), 2.77 (s, 3H), 2.70 (dt, J=4.5, 7.2 Hz, 2H),2.27-2.11 (m, 5H), 2.00 (s, 3H);

¹³C NMR (d₆-DMSO) δ=167.60, 165.95, 150.10, 149.03, 139.13, 137.38,136.05, 134.72, 133.79, 133.13, 132.47, 129.65, 129.33, 124.86, 124.20,123.65, 116.37, 56.80, 36.52, 34.45, 28.74, 19.43, 19.32;

MS (ES): m/e 528 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=3.74 min.

Example 224 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-4-methyl-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(piperidin-4-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-4-methyl-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamideusing Method L (Step A).

¹H NMR (d₆-DMSO HCl salt) δ=7.91 (t, J=5.4 Hz, 1H), 7.46-7.40 (m, 3H),7.34 (s, 1H), 7.24 (t, J=7.8 Hz, 1H), 7.12 (d, J=7.8 Hz, 1H), 4.99 (dd,J=4.5, 9.9 Hz, 1H), 3.35-3.12 (m, 3H), 2.95-2.83 (m, 3H), 2.69 (s, 3H),2.26-2.22 (m, 4H), 2.10-2.06 (m, 1H), 1.92 (s, 3H), 1.87-1.21 (m, 7H);

MS (ES): m/e: 534 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=3.76 min.

Example 225 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-4-methyl-1,2,3,4-tetrahydro-quinoxalin-2-yl]-N-[2-(N-methyl-1,2,5,6-tetrahydropyrid-4-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-4-methyl-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamideby Method J.

¹H NMR (d₆-DMSO HCl salt) δ=8.02-7.99 (m, 1H), 7.47-7.41 (m, 4H),7.30-7.25 (m, 1H), 7.16 (d, J=8.1 Hz, 1H), 5.43-5.38 (m, 1H), 5.05-4.99(m, 1H), 3.70-3.47 (m, 3H), 3.22-2.97 (m, 3H), 2.77-2.74 (m, 6H),2.60-2.47 (m, 1H), 2.33-2.16 (m, 6H), 2.13-2.07 (m, 2H), 1.98-1.97 (s,3H);

MS (ES): m/e 545 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=3.85 min.

Example 226 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-6,7-dichloroquinoxalin-2-yl]-N-benzylacetamide

4,5-Dichlorobenzene-1,2-diamine was reacted with N-benzylmaleimide usingMethod F, followed by condensation with4-chloro-2,5-dimethyl-benzenesulfonyl chloride using Method G.

¹H NMR (DMSO-d₆) δ=2.09 (s, 3H), 2.24(s, 3H), 2.32(m, 2H), 4.00 (dd, J=6Hz, 1H), 4.32 (dd, J=6 Hz, 1H), 4.83(dd, J=6 Hz, 1H),7.01-7.54 (m, Ar—H,9H), 8.37(t, J=5.7 Hz, 1H), 10.76(s, 1H);

MS (ES): m/e 568.1 (M+H), 590.1(M+Na).

Example 227 Preparation of2-[2-(R,S)-1-(2,4,6-trimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-6,7-dichloroquinoxalin-2-yl]-N-benzylacetamide

4,5-Dichlorobenzene-1,2-diamine was reacted with N-benzylmaleimide usingMethod F, followed by condensation with 2,4,6-trimethyl-benzenesulfonylchloride using Method G to afford the title compound.

¹H NMR (DMSO-d₆) δ=15-2.50 (dd, and s, 1H), 4.05 (dd, J=5.4 Hz, 1H),4.25 (dd, J=5.4 Hz, 1H), 4.68 (dd, J=5.4 Hz, 1H), 7.02-7.31(m, Ar—H,7H), 8.34 (t, 1H), 10.93(s, 1H);

MS (ES): m/e 547 (M+H), 569 (M+Na).

Example 228 Preparation of2-[2-(R,S)-1-(2,4,6-trimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-6,7-dimethylquinoxalin-2-yl]-N-benzylacetamide

4,5-Dimethylbenzene-1,2-diamine reacted with N-benzylmaleimide usingMethod F. The resulting product reacted with2,4,6-trimethyl-benzenesulfonyl chloride using Method G to afford thedesired material.

¹H NMR (DMSO-d₆): δ=2.04-2.30(m, 17H), 3.29 (d, 1H), 4.10 (dd, 2H), 4.71(dd, 1H), 6.68-7.30(m, 4H), 8.28(t, 1H, NH), 10.48(s, NH);

MS (ES): m/e 506.3,(M+H), 528.3 (M+Na);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=4.11 min.

Example 2292-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-6,7-dimethylquinoxalin-2-yl]-N-benzylacetamide

The title compound was prepared from 4,5-dimethyl 1,2-phenylene-diamineusing Method F, followed by Method G using 2,5-dimethyl4-chloro-benzenesulfonyl chloride.

¹H NMR (DMSO-d₆) δ=2.0-2.5 (dd, m, s 14H), 4.15(dd, J=14.5 Hz, 1H), 4.3(dd, J=14.5 Hz, 1H), 4.89 (dd, J=4.5 Hz, 1H), 7.14-7.49 (m, ArH, 8H),8.36(t, 1H, NH), 10.35 (s, 1H, NH);

MS (ES): m/e 527 (M+H), 549 (M+Na).

Example 230 Preparation of2-[2-(R,S)-1-(2,4,6-trimethylbenzenesulfonyl)-3-oxo-4-methyl-1,2,3,4-tetrahydroquinoxalin-2-yl]N-benzylacetamide

N-Methyl-benzene-1,2-diamine reacted with N-benzylmaleimide using MethodF. The resulting product reacted with 2,4,6-trimethylbenzenesulfonylchloride using Method G to afford the title material.

¹H NMR (DMSO-d₆) δ=2.14-2.30 (m, 2H), 2.24 (s, 9H), 2.98 (s, 3H),3.72-4.53 (m, 2H), 4.92 (dd, 1H), 7.06-7.41 (m, 1H), 8.34 (t, 1H, NH);

MS (ES): m/e 492 (M+H), 541 (M+Na);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=5.64 min.

Example 231 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamide

2-[2-(R,S)-1-(4-Chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid reacted with 2-pyridin-4-ylethylamine using Method I to afford thetitle material.

¹H NMR (DMSO-d₆) δ=1.90-2.20 (m, s, 8H), 2.64 (t, 2H), 3.19-3.51 (m,2H), 4.85 (dd, 1H), 6.79-7.46 (m, Ar—H, 8H), 7.98 (t, 1H), 8.44 (d, 2H),10.45 (s, 1H);

MS (ES): m/e 514(M+H), 536 (M+Na);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=3.28 min.

Example 232 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(N-methylpiperidin-4-yleth-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamidewas subjected to Method J and Method K to afford the title material asan HCl salt.

¹H NMR (DMSO-d₆) δ=1.0-1.15 (m, 2H), 1.65 (bd, 2H), 1.80(t, 2H),1.95-2.20(m, 2H), 2.0(s, 3H), 2.09(s, 3H), 2.21 (s, 3H), 2.70(bd, 2H),2.90(m, 2H), 3.10 (m, 2H), 4.83 (dd, 1H), 6.80-7.44(m, ArH, 6H), 7.81(t,1H, NH);

MS (ES): m/e 534 (M+H), 556 (M+Na).

Example 233 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(piperidin-4-yl)eth-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamidewas subjected to Method L (Step A) to afford the title material as anHCl salt.

¹H NMR (DMSO-d₆)) δ=1.28 (m, 2H), 1.83 (t, 2H), 2.0-2.10(m, 2H), 1.96(s, 3H), 2.20 (s, 3H), 2.75-2.90(br m, 4H), 3.05-3.40 (bm, 4H), 4.85(dd, 1H), 6.81 (s, 1H, Ar), 6.83 (s, 1H, Ar), 7.11-7.40 (m, 5H, ArH),7.95 (t, NH), 8.82 (br t, NH), 8.95 (b t, NH), 10.41 (s, NH);

MS (ES): m/e 520 (M+H).

Example 234 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl-N-oxide)eth-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamidereacted with m-chloroperbenzoic acid (1.0 eq) in dioxane to afford thetitle material.

¹H NMR (DMSO-d₆) δ=1.99(s, 3H), 2.10-2.15(m, 2H), 2.10 (s, 3H), 2.65 (m,2H) 3.20(m, 2H), 4.84 (dd, J=4.8 Hz, 1H), 6.80-7.36 (m, 8H, ArH), 7.40(s, 1H), 7.95(t, 1H, NH),8.05(d, 2H), 10.46 (s, 1H, NH);

MS (ES): m/e 530 (M+H), 552 (M+Na);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=3.21 min.

Example 2352-[2-(R,S)-1-(2,6-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetra-hydroquinoxalin-2-yl]-N-benzylacetamide

Benzene-1,2-diamine reacted with N-methylmaleimide using Method F. Theresulting product reacted with 2,6-dichlorobenzenesulfonyl using MethodG to afford the title material.

¹H NMR (DMSO-d₆) δ=2.32-2.45(m, 2H), 4.18(m, 2H), 5.14(dd, J=5.7 Hz,1H), 6.80-7.60(m, Ar—H, 1H), 8.34(t, J=3.6 Hz, 1H), 10.63(s, 1H);

MS (ES): m/e 504 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=26.5 min.

Example 236 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-methylenecarbonyl-(4-methylpiperazin-1-yl)

2-[2-(R,S)-3-Oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]acetic acid wasreacted with N-methylpiperazine using Method D. The resulting productwas then reacted with 4-chloro-2,5-dimethylbenzenesulfonyl chlorideusing Method G to afford the title product.

¹H NMR (DMSO-d₆) δ=1.98(s, 1.5H), 2.0(1.5H), 2.26(s, 3H), 2.40-3.05(m,1H), 3.2-3.8(m, 4H), 4.9(bd, 1H), 6.82-7.47(m, 6H), 10.55(s, 0.5H),10.57(s, 0.5H);

MS (ES): m/e 492 (M+H).

Example 237 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-methylpiperazin-1-yl)eth-1-yl]acetamide

2-Chloroethylamine hydrochloride was reacted with 1-methylpiperazine inwater. After evaporation of the water, the resulting amine was reactedwith2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]aceticacid using Method I. The product was isolated from preparative HPLC as aTFA salt.

¹H NMR (DMSO-d₆) δ=2.04 (s, 3H), 2.10-2.40(m, 2H), 2.27(s, 3H), 2.80(s,3H), 2.6-3.5 (bm, 6H), 4.93 (dd, J=3.9 Hz), 6.86-7.50(m, Ar—H, 6H),8.15(bt, 1H), 10.53(s, 1H);

MS (ES): m/e 535 (M+H).

Example 238 Preparation of 2-[2-(R,S)1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(2-chloroeth-1-yl)acetamide

The title compound was prepared using2-[2-(R,S)-1-(4-chloro-2,5-di-methylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid was treated with chloroethyl amine using Method I.

¹H NMR (DMSO-d₆) δ=2.00(s, 3H), 2.22(s, 3H), 2.10-2.30(m, 2H), 3.30(bt,2H), 3.51(bt, 2H), 4.85(dd, J=4.8 Hz), 6.90-7.60(m, Ar—H, 6H), 8.21(bt,1), 10.50(s, 1H);.

MS (ES): m/e 470.0(M+H), 492.0(M+Na);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=5.33 min.

Example 239 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(N-methyl-1,2,5,6-tetrahydropyrid-4-yl)eth-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamidewas subjected to Method J to afford the title material.

¹H NMR (DMSO-d₆) δ=1.97-2.19 (m, 2H), 2.07(s, 3H), 2.19(s, 3H), 2.35(s,3H), 2.38(bt, 2H), 2.85-3.13(m, 6H), 4.84(dd, J═Hz, 1H), 5.31(s, 1H),6.79-7.41(m, Ar—H, 6H), 7.81 (t, J═Hz, 1H), 10.44 (s, 1H);

MS (ES): m/e 532 (M+H).

Example 240 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(N-cyclopropylpiperidin-4-yl)eth-1-yl]acetamide

Reaction of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(piperidin-4-yl)eth-1-yl]acetamidewith 1-ethoxy-1-trimethysiloxy cyclopropane using Method L gave thetitle material.

¹H NMR (DMSO-d₆) δ=0.21 (bd, 2H), 0.34(bd, 2H), 0.90-1.85(m, 5H),1.9-2.4(m, 2H), 2.20(s, 3H), 2.45(s, 3H), 3.00(m, 2H), 3.30(m, 6H),4.81(dd, J=4.5 Hz, 1H), 6.77-7.41(m, Ar—H, 6H), 7.76(bt, 1H), 10.40(s,1H);

MS (ES): m/e 560 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=3.60 min.

Example 241 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-methoxycarbonyl-2-pyrid-4-yl)eth-1-yl]acetamide

2-t-Butoxycarbonylamino-3-(R)-pyridin-4-yl-propionic acid was convertedto its methyl ester using Method P. The resulting ester reacted with2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]aceticacid using Method I to afford the title product.

¹H NMR (DMSO-d₆) δ=1.92 (s, 3H), 1.96(s, 3H), 2.22(bm, 5H), 2.80-3.40(m,2H), 3.58(s, 3H), 3.61(s, 3H), 4.48(m, 1H), 4.80(bd, 1H), 6.77-7.41(m,Ar—H, 8H), 8.43(brd, 1H), 8.49(d, 2H), 10.44(s, 1H);

MS (ES): m/e 571.0(M+H), 592.6 (M+Na);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=3.19, 4.21 min.(provided a pair of diastereomers).

Example 242 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(methoxycarbonyl)-2-(N-methyl-1,2,3,6-tetrahydropyrid-4-yl)eth-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-methoxycarbonyl-2-pyrid-4-yl)eth-1-yl]acetamidewas subjected to Method J to afford the title compound.

¹H NMR (DMSO-d₆) δ=1.98 (s, 3H), 2.20 and 2.24 (s, 3H), 2.24(m, 2H),2.33(m, 4H), 2.70(bd, 2H), 3.29(bm, 2H), 3.60 and 3.56 (s, 3H), 4.28 (m,1H), 4.82(m, 1H), 5.32(bd, 1H), 6.78-7.43(m, Ar—H, 6H), 8.24(t, 1H),10.43 (bs, 1H);

MS (ES): m/e 590 (M+H), 611.8 (M+Na).

Example 243 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(methoxycarbonyl)-2-(N-methylpiperidin-4-yl)eth-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(methoxycarbonyl)-2-(N-methyl-1,2,3,6-tetrahydropyrid-4-yl)eth-1-yl]acetamidesubjected to Method K to afford the title compound as a diastereomericmixture.

¹H NMR (DMSO-d₆) δ=0.9-1.40(m, 9H), 1.97(s, 3H), 2.16, 2.21(s, 3H),2.24(s, 3H), 2.74(bt, 2H), 3.58 and 3.61(s, 3H), 4.22, 4.32 (m, 1H),4.86 (m, 1H), 6.80-7.47(m Ar—H, 6H), 8.31(t, 1H), 10.43 (bt, 1H);

MS (ES): m/e 592 (M+H), 614 (M+Na););

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=3.40 min.

Example 244 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(α,α-dimethylglycine)piperidin-4-yl]eth-1-yl}acetamide

2-t-Butoxycarbonylamino-2-methyl-propionic acid reacted with2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]-N-[2-(piperidin-4-yl)eth-1-yl]acetamideusing Method I followed by cleavage of the tert-butoxycarbonyl groupusing neat TFA at room temperature for a few hours. The title compoundwas isolated in good yields.

¹H NMR (DMSO-d₆) δ=0.94-1.85(bm, 4H), 1.51 (s, 6H), 1.90 (s, 3H), 2.1(s, 3H), 2.10-2.47 (m, 2H), 2.70-3.11(m, 4H), 4.35(bt, 4H), 4.84(dd,1H), 7.41-7.79(m, 6H, ArH), 7.86(bt, NH), 8.06, (bt, NH2), 10.43(s, NH);

LCMS 605 (M+H).

Example 245 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(α-aminoacetyl)piperidin-4-yl]eth-1-yl}acetamide

t-Butoxycarbonylamino-acetic acid reacted with2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(piperidin-4-yl)eth-1-yl]acetamideusing Method I followed by cleavage of the tert-butoxycarbonyl groupusing TFA at room temperature for a few hours. The title compound wasisolated in good yields.

¹H NMR (DMSO-d₆) δ=0.9-1.30(m, 4H), 1.30(m, 2H), 1.75(m, 2H), 1.98(s,3H), 2,07-2.27 (m, 2H), 2.15 (s, 3H), 2.67(bt, 2H), 3.69(bd, 2H),3.69(bt, 2H), 3.85(bt, 2H), 4.40(bt, 2H), 4.87(dd, J=3.9 Hz),6.81-7.43(m, Ar—H, 6H), 7.88(br. t, 1H), 7.98(bt, NH2), 10.45(s, 1H);

MS (ES): m/e 577 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=5.20 min.

Example 246 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[(piperidin-1-yl)carbonylmethyl]acetamide

t-Butoxy carbonyl glycine was condensed with piperidine using Method S.The resulting amide was treated with neat TFA at room temperature for afew hours. TFA was evaporated under reduced pressure, and the resultingamine was condensed with2[2-(R,S)-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid using Method S, to provide the desired material in good yield.

¹H NMR (DMSO-d₆) δ=9.63 (s, 1H), 7.20 (m, 1H), 6.63 (s, 1H), 6.55 (m,2H), 6.29 (m, 1H), 5.99 (m, 1H), 4.05 (m, 1H), 3.02 (m, 2H), 2.55 (m,2H), 2.47 (s, 2H), 1.65 (m, 2H), 1.40 (s, 3H), 1.18 (s, 3H), 0.58 (m,6H).

MS (ES): m/e 533.1 (M+H), 555.1 (M+Na).

Example 247 Preparation of 2-[2-(R orS-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-2-phenyl-1-(methoxycarbonyl)eth-1-yl]acetamide

D-phenylalanine methyl ester hydrochloride salt was condensed to2[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]aceticacid using Method S to provide the desired material in good yields.

¹H NMR (CDCl₃) δ=8.78 (s, 1H), 7.59 (m, 2H), 7.31 (m, 5H), 7.19 (m, 4H),6.85 (m, 1H), 6.58 (m, 1H), 5.15 (m, 1H), 4.90 (m, 1H), 3.79 (s, 3H),2,93 (m, 2H), 2.52 (m, 2H), 2.31 (s, 3H), 2.01 (s, 3H);

MS (ES): m/e 571 (M+H), 593 (M+Na).

Example 248 Preparation of 2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-1-pyrrolidin-N-ylcarbonyl-2-phenyleth-1-yl]acetamide

t-Butoxy carbonyl D-phenylalanine was condensed with pyrrolidine usingMethod S. The resulting amide was treated with neat TFA at roomtemperature for a few hours. TFA was evaporated under reduced pressure,and the resulting amine was condensed with2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid using Method S, to provide the desired material in good yield.

¹H NMR (CDCl₃) δ=9.09 (s, 1H), 7.71 (m, 3H), 7.26 (m, 9H), 6.87 (m, 1H),5.20 (m, 1H), 5.01 (m, 1H), 3.41 (m, 1H), 3.04 (m, 1H), 2.98 (m, 2H),2.72 (m, 1H), 2.61 (m, 2H), 2.47 (m, 1H), 2.31 (s, 3H), 2.18 (s, 3H),1.70 (m, 4H);

MS (ES): m/e 610 (M+H), 632 (M+Na).

Example 249 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-hydroxyphenyl)-1-(S)-(methoxycarbonyl)eth-1-yl]acetamide

L-tyrosine methyl ester hydrochloride salt was condensed to2[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid using Method S.

HPLC (acetonitrile/water): R_(t)=4.80, 4.99 min.

Example 250 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-phenyl-1-(S)-(methoxycarbonyleth-1-yl]acetamide

L-phenylalanine methyl ester hydrochloride salt was condensed to2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]aceticacid using Method S.

HPLC (acetonitrile/water 6:3) R_(t)=14.91, 15.26 min.

Example 251 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-cyanophenyl)1-(R)-(pyrrolidin-N-ylcarbonyl)eth-1-yl]acetamide

t-Butoxycarbonyl-D-p-cyanophenylalanine was condensed with pyrrolidineusing Method S. The resulting amide was treated with neat TFA at roomtemperature for a few hours. TFA was evaporated under reduced pressure,and the resulting amine was condensed with2-[2-(R,S)-1-(4-chloro-2,5-dimethyl-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid using Method S, to provide the desired material in good yield.

MS (ES): m/e 635 (M+H), 658 (M+Na).

Example 252 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(phenyl)-1-(S)-(pyrrolidin-N-ylcarbonyl)eth-1-yl]-N-methylacetamide

t-Butoxycarbonyl-L-phenylalanine was condensed with pyrrolidine usingMethod S. The resulting amide was treated with neat TFA at roomtemperature for a few hours. TFA was evaporated under reduced pressure,and the resulting amine was condensed with2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzene-sulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid using Method S, to provide the desired material in good yield.

¹H NMR (CDCl₃) δ=9.85 (s, 1H), 9.25 (s, 1H), 7.63 (m, 1H), 5.12 (m, 1H),4.90 (m, 1H), 3.24 (m, 8H), 2.18 (d, 3H), 2.09 (d, 3H), 1.45 (m, 4H).

Example 253 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(2-phenyl-1-(R)-carboxy-eth-1-yl)acetamide

This compound was obtained from2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-2-phenyl-1-(methoxycarbonyl)eth-1-yl]acetamideusing Method C.

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=10.37, 11.54 min.

Example 2542-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-hydroxyphenyl)-1-(R)-(methoxycarbonyl)eth-1-yl]acetamide

D-tyrosine methyl ester hydrochloride salt was condensed to2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid using Method S to provide the desired material in good yields.

MS (ES): m/e 587 (M+H), 609 (M+Na).

Example 255 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-methylacetamide

Methylamine hydrochloride salt was condensed to2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]aceticacid using Method S.

¹H NMR (CDCl₃) δ=7.67 (m, 2H), 7.56 (s, 1H), 7.24 (m, 1H), 7.16 (m),6.74 (m, 1H), 6.00 (m, 1H), 5.04 (m, 1H), 2.78 (s, 3H), 2.58 (m, 2H),2.26 (s, 3H), 2.04 (s, 3H);

MS (ES): m/e 423 (M+H), 444 (M+Na).

Example 256 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-cyanophenyl)-1-(S-(pyrrolidin-N-ylcarbonyl)eth-1-yl]acetamide

t-Butoxycarbonyl-L-p-cyanophenylalanine was condensed with pyrrolidineusing Method S. The resulting amide was treated with neat TFA at roomtemperature for a few hours. TFA was evaporated under reduced pressure,and the resulting amine was condensed with2-[2-(R,S)-1-(4-chloro-2,5-dimethyl-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid using Method S, to provide the desired material in good yield.

HPLC ((CH₃CN—H₂O-0.1% TFA) R_(t)=11.66, 12.03 min.

Example 257 Preparation of2-[2-(S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(t-butoxycarbonyl)-2-(phenyl)eth-1-yl]acetamide

D-phenylalanine t-butyl ester hydrochloride salt was condensed to2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]aceticacid using Method S to provide the desired material in good yields.

¹H NMR (CDCl₃) δ=9.08 (s, 1H), 9.02 (s, 1H), 7.53 (m, 2H), 7.30 (m, 8H),6.80 (m, 2H), 6.50 (d, 1H), 6.40 (d, 1H), 5.12 (m, 1H), 4.75 (m, 1H),3.10 (m, 2H), 2.50 (m, 1H), 2.33 (m, 1H), 2.19 (d, 3H), 2.04 (d, 3H),1.38 (s, 9H), 1.39 (s, 9H).

Example 258 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(isopropoxycarbonyl)-2-(phenyl)eth-1-yl]acetamide

D-phenylalanine iso-propyl ester hydrochloride salt was condensed to2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]aceticacid using Method S to provide the desired material in good yield.

¹H NMR (CDCl₃) δ=9.23 (s, 1H), 9.05 (s, 1H), 7.51 (m, 2H), 7.20 (m, 8H),6.77 (m, 2H), 6.55 (m, 1H), 5.11 (m, 1H), 5.05 (m, 1H), 4.81 (m, 1H),3.10 (m, 2H), 2.50 (m, 1H), 2.32 (m, 1H), 2.19 (s, 3H), 2.04 (s, 3H),1.23 (d, 2H), 1.12 (d, 2H).

Example 259 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{1-(S)-[pyrrolidin-N-ylcarbonyl]-2-[4-(2-imidazolin-2-yl)phenyl]eth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetra-hydroquinoxalin-2-yl]-N-[2-(4-cyanophenyl)-1-(S)-(pyrrolidin-N-ylcarbonyl)eth-1-yl]acetamideand ethylenediamine were submitted to Method T, and the desired materialisolated as a TFA salt upon HPLC purification.

HPLC (acetonitrile/water-0.1% TFA 3:6): R_(t)=5.49 mn.

Example 260 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N,N-diisopropylacetamide

N,N-diisopropyl amine was condensed to2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid using Method S.

¹H NMR (CDCl₃) δ=8.11 (s, 1H), 7.63 (d, 1H), 7.55 (s, 1H), 7.20 (t, 1H),7.05 (t, 1H), 6.75 (d, 1H), 5.10 (t, 1H), 3.83 (m, 1H), 3.4 (m, 1H),2.61 (d, 2H), 2.24 (s, 3H), 2.11 (s, 3H), 1.30 (d, 3H), 1.22 (d, 3H),1.18 (d, 6H).

Example 261 Preparation of 2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[(4-imidazolin-2-yl)phenyl]-1-(R)-(pyrrolidin-N-ylcarbonyl)eth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-cyanophenyl)-1-(R)-(pyrrolidin-N-ylcarbonyl)eth-1-yl]acetamideand ethylenediamine were submitted to Method T, and the desired materialisolated as one diastereomer, upon prep HPLC purification.

HPLC (acetonitrile/water-0.1% TFA): R_(t)=3.69 min;

MS (ES): m/e 678 (M+H).

Example 262 Preparation of 2-[2-(R orS)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[4-(imidazolin-2-yl)phenyl-1-(R)-(pyrrolidin-1-ylcarbonyl)eth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetra-hydroquinoxalin-2-yl]-N-[2-(4-cyanophenyl)-1-(R)-(pyrrolidin-N-ylcarbonyl)eth-1-yl]acetamideand ethylenediamine were submitted to Method T, and the desired materialisolated as one diastereomer, upon prep HPLC purification.

HPLC (acetonitrile/water-0.1% TFA): R_(t)=3.89 min;

MS (ES): m/e 678 (M+H).

Example 263 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-methylenecarbonyl-(2-(R,S)-methylpiperidin-N-yl)

The title compound was obtained using Method W starting with2-(R,S)-methylpiperidine and2-[2-(R,S)-1-(4-chloro-2,5-dimethylphenylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid.

MS (ES): m/e 491 (M+H).

Example 264 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-methlenecarbonyl-[4-acetiylpiperazin-1-yl]

The title compound was obtained using Method W, starting with4-acetylpiperazine and2-[2-(R,S)-1-(4-chloro-2,5-dimethylphenylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid.

MS (ES): m/e 520 (M+H).

Example 265 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenestilfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N,N-di(2-methoxyeth-1-yl)acetamide

The title compound was obtained using Method W, starting with2-methoxyethylamine and2-[2-(R,S)-1-(4-chloro-2,5-dimethylphenylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid.

MS (ES): m/e 525 (M+H).

Example 266 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-cyclohexyl-N-ethylacetamide

The title compound was obtained using Method W, starting withN-cyclohexyl-N-ethylamine and2-[2-(R,S)-1-(4-chloro-2,5-dimethylphenyl-sulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid.

MS (ES): m/e 519 (M+H).

Example 267 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-methylenecarbonyl-[4-(R,S)-hydroxypiperidin-N-yl]

The title compound was obtained using Method W, starting with2-[2-(R,S)-1-(4-chloro-2,5-dimethylphenylsulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]aceticacid and hydroxypiperidine.

MS (ES): m/e 493 (M+H).

Example 268 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N,N-diethylacetamide

The title compound was obtained using Method W, starting with2-[2-(R,S)-1-(4-chloro-2,5-dimethylphenylsulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]aceticacid and N,N-diethylamine.

MS (ES): m/e 465 (M+H).

Example 269 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-phenethyl-N-methylacetamide

The title compound was obtained using Method W, starting with2-[2-(R,S)-1-(4-chloro-2,5-dimethylphenylsulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]aceticacid and N-phenethyl-N-methylamine.

MS (ES): m/e 527 (M+H).

Example 270 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-methylenecarbonyl-[3-(R,S)-carboxamide-piperidin-N-yl]

The title compound was obtained using Method, starting with2-[2-(R,S)-1-(4-chloro-2,5-dimethylphenylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and 3-(R,S)-carboxamide-piperidine.

MS (ES): m/e 520 (M+H).

Example 271 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-methylenecarbonyl-[2-(S)-hydroxymethylpyrrolidin-N-yl]

The title compound was obtained using Method W, starting with2-[2-(R,S)-1-(4-chloro-2,5-dimethylphenylsulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]aceticacid and 2-(S)-hydroxymethylpyrrolidine.

MS (ES): m/e 493 (M+H).

Example 272 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-methylenecarbonyl-[2-(S)-methoxymethylpyrrolidin-1-yl]

The title compound was obtained using Method W, starting with2-[2-(R,S)-1-(4-chloro-2,5-dimethylphenylsulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]aceticacid and [2-(S)-methoxymethylpyrrolidine.

MS (ES): m/e 507 (M+H).

Example 273 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(n-hexyl)-N-methylacetamide

The title compound was obtained using Method W, starting with2-[2-(R,S)-1-(4-chloro-2,5-dimethylphenylsulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]aceticacid and N-methyl hexylamine.

MS (ES): m/e 513 (M+H).

Example 274 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-hydroxyphenyl)-1-(S)-(t-butoxyoxycarbonyl)eth-1-yl]acetamide

The title compound was prepared from2-[2-(R,S)-1-(4-chloro-2,5-dimethylphenylsulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]aceticacid and L-tyrosine t-butyl ester hydrochloride salt using Method Y.

HPLC (acetonitrile/water-0.1% TFA): R_(t)=30.0, 31.1 min.

Example 275 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-methylenecarbonyl-[2-(S)-methoxycarbonylpyrrolidin-N-yl]

The title compound was prepared using Method X, starting with2-[2-(R,S)-1-(4-chloro-2,5-dimethylphenylsulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]aceticacid and 2-(S)-methoxycarbonylpyrrolidine.

HPLC (acetonitrile/water-0.1% TFA): R_(t)=27.41,27.5 min.

Example 276 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(S)-carboxamide-2-(S)-methylbut-1-yl]acetamide

The title compound was prepared using Method X, starting with2-[2-(R,S)-1-(4-chloro-2,5-dimethylphenylsulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]aceticacid and 1-(S)-carboxamide-2-(S)-methylbut-1-ylamine.

HPLC (acetonitrile/water-0.1% TFA): R_(t)=25.7, 26.27 min.

Example 277 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-methoxycarbonylmethylacetamide

The title compound was prepared using Method X, starting with2-[2-(R,S)-1-(4-chloro-2,5-dimethylphenylsulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]aceticacid and N-methoxycarbonylmethylamine.

HPLC (acetonitrile/water-0.1% TFA): R_(t)=25.12; 25.2 min.

Example 278 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-carboxamide-2-(phenyl)eth-1-yl]acetamide

The title compound was prepared from2-[2-(R,S)-1-(4-chloro-2,5-dimethylphenylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and 2-phenylalanine carboxamide hydrochloride salt using Method Z.

HPLC (acetonitrile/water-0.1% TFA): R_(t)=3.29; 3.37 min.

Example 279 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-methylenecarbonyl-[2-(R)-hydroxy-5-(S)-methoxycarbonylpyrrolidin-N-yl]

The title compound was prepared from2-[2-(R,S)-1-(4-chloro-2,5-dimethylphenylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and 2-(R)-hydroxy-5-(S)-methoxycarbonylpyrrolidine using Method Z.

HPLC (acetonitrile/water-0.1% TFA): R_(t)=2.64 min.

Example 280 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-(methoxycarbonyl)eth-1-yl]acetamide

The title compound was prepared from2-[2-(R,S)-1-(4-chloro-2,5-dimethylphenylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and D-alanine methyl ester hydrochloride salt using Method Z.

HPLC (acetonitrile/water-0.1% TFA): R_(t)=3.17, 3.23 min.

Example 281 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(S)-(t-butoxycarbonyl)-3-methylbut-1-yl]acetamide

The title compound was prepared from2-[2-(R,S)-1-(4-chloro-2,5-dimethylphenylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and L-leucine t-butyl ester hydrochloride salt using Method Z.

HPLC (acetonitrile/water-0.1% TFA): R_(t)=5.50 min.

Example 282 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(S)-1,3-dicarboxamideprop-1-yl]acetamide

The title compound was prepared from2-[2-(R,S)-1-(4-chloro-2,5-dimethylphenylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and L-asparagine carboxamide hydrochloride salt using Method Z.

HPLC (acetonitrile/water-0.1% TFA) R_(t)=2.29 mn.

Example 283 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-1,3-di(benzyloxy-carbonyl)prop-1-yl]acetamide

The title compound was prepared from2-[2-(R,S)-1-(4-chloro-2,5-dimethylphenylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and D-glutamic acid dibenzyl ester hydrochloride salt using MethodZ.

HPLC (acetonitrile/water-0.1% TFA): R_(t)=5.65 min.

Example 284 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(3-t-butoxycarbonyl-1-methoxycarbonylprop-1-yl)acetamide

The title compound was prepared from2-[2-(R,S)-1-(4-chloro-2,5-dimethylphenylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and L-glutamic acid methyl ester P-t-butyl ester hydrochloride saltusing Method Z.

HPLC (acetonitrile/water-0.1% TFA): R_(t)=4.58 min.

Example 285 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(S)-ethoxycarbonyleth-1-yl]acetamide

The title compound was prepared from2-[2-(R,S)-1-(4-chloro-2,5-dimethylphenylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and L-alanine ethyl ester hydrochloride salt using Method Z.

HPLC (acetonitrile/water-0.1% TFA): R_(t)=3.65 min.

Example 286 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(S)-carboxamide-2-(indol-3-yl)eth-1-yl]acetamide

The title compound was prepared from2-[2-(R,S)-1-(4-chloro-2,5-dimethylphenylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and tryptophan carboxamide hydrochloride salt using Method Z.

HPLC (acetonitrile/water-0.1% TFA): R_(t)=3.28 min.

Example 287 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(R)-methoxycarbonylphenylmethyl)]acetamide

The title compound was prepared from2-[2-(R,S)-1-(4-chloro-2,5-dimethylphenylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and D-phenylglycine methyl ester using Method Z.

HPLC (acetonitrile/water-0.1% TFA): R_(t)=4.21 min.

Example 288 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-methylenecarbonyl-[2-(R)-methoxycarbonylpyrrolidin-N-yl

The title compound was prepared from2-[2-(R,S)-1-(4-chloro-2,5-dimethylphenylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and D-proline methyl ester hydrochloride salt using Method Z.

HPLC (acetonitrile/water-0.1% TFA): R_(t)=3.49 min.

Example 289 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(indol-3-yl)-1-(R)-(methoxycarbonyl)eth-1-yl]acetamide

The title compound was prepared from2-[2-(R,S)-1-(4-chloro-2,5-dimethylphenylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and D-typrtophan methyl ester hydrochloride salt using Method Y.

HPLC (acetonitrile/water-0.1% TFA): R_(t)=30.3, 30.43 min.

Example 290 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(S)-carboxamide-2-(phenyl)eth1-yl]acetamide

The title compound was prepared from²-[²-(R,S)-1-(4-chloro-2,5-dimethylphenylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and L-phenylalanine carboxamide hydrochloride salt using Method X.

HPLC (acetonitrile/water-0.1% TFA): R_(t)=3.29, 3.37 min.

Example 291 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[1-(S-(t-butoxycarbonyl)-2-(4-hydroxyphenyl)eth-1-yl]acetamide

The title compound was prepared from2-[2-(R,S)-1-(4-chloro-2,5-dimethylphenylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and L-tyrosine t-butyl ester hydrochloride salt using Method X.

Example 292 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(N-methyl-1,2,5,6-tetrahydro-pyrid-4-yl)-1-(R)-(pyrrolidin-N-ylcarbonyl)eth-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]-N-[2-(pyrid-4-yl)-1-(R)-(pyrrolidin-N-ylcarbonyl)eth-1-yl]acetamidewas converted to the title compound by Method J.

¹H NMR (DMSO-d₆) δ=1.8-2.2 (m, 6H), 2.89 (bd, 2H), 3.10-3.60(m, 8H),4.6(m, 1H), 4.83(m, 1H), 5.26(bd, 1H), 5.34(bd), 6.78-7.40(m, Ar—H, 6H),8.14(d, J=7.5 Hz1H), 10.42(s, 1H), 10.44(s, 1H);

MS (ES): m/e 629 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=4.39 min.

Example 293 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(N-methylpiperidin-4-yl)eth-1-yl]-N-isopropylacetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]-N-isopropylacetamidewas subjected to Methods J and K to afford the title material.

¹H NMR (DMSO-d₆) δ=0.81-1.28(m, 12H), 1.66-1.78(m, 1H), 2.04(s, 3H),2.15(s, 3H), 2.20(s, 3H), 2.10-2.45(m, 2H), 2.50-3.13(m, 6H)3.70(m, 1H),4.41(m, 1H), 4.90(m, 1H), 6.80-7.46(m, 6H), 10.51(s, 1H), 10.54(s, 1H);

MS (ES): m/e 576 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column) R_(t)=4.01 min.

Example 294 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(N-phenylpiperidin-4-yl)eth-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(piperidin-4-yl)eth-1-yl]acetamidereacted with triphenylbismuth diacetate using Method M which led to thetitle material.

¹H NMR (DMSO-d₆) δ=1.75-1.13(m, 7H), 2.02(s, 3H), 2.24(s, 3H),2.00-2.28(m, 2H), 2.69(bt, 2H), 3.18(m, 2H), 3.70(bd, 2H), 4.81(dd, J=6Hz, 1H), 6.71-7.47(m, Ar—H, 1H), 7.89(t, J=3.0 Hz, 1H), 10.47(s, 1H);

MS (ES): m/e 596 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=5.59 min.

Example 295 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(N-methylpiperidin-4-yl)eth-1-yl]-N-methylacetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]-N-methylacetamidewas subjected to Methods J and K to afford the title material.

¹H NMR (DMSO-d₆) δ=1.34-1.95(m, 7H), 1.96(s, 3H), 2.23(s, 3H),2.0-2.47(m, 2H), 2.95-3.50(m, 6H), 3.00(s, 3H), 3.05(s, 3H), 4.86(m,1H), 6.79-7.40(m, Ar—H, 6H), 7.91 (bt, 1H), 10.44(s, 1H);

MS (ES): m/e 548 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=3.70 min.

Example 296 Preparation of 2-[2-(R,S)1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]-N-methylacetamide

The title compound was obtained by reactingmethyl-(2-pyridin-4-yl-ethyl)-amine with2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid using Method I.

¹H NMR (DMSO-d₆) δ=1.97(s, 3H), 2.20(s, 3H), 2.38-2.47(m, s, 2.67(s,3H), 2.60-2.74(m, 5H),3.25-3.47(m, 4H), 4.88(m, 1H), 6.78-7.44(m, Ar—H,8H), 8.31-8.43(dd, 2H), 10.48, 10.50(s, 1H);

MS (ES): m/e 528 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=3.53 min.

Example 297 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)-1-(R)-(pyrrolidin-N-ylcarbonyl)eth-1-yl]acetamide

(R)-2-t-Butoxycarbonylamino-3-pyridin-4-yl-propionic acid reacted withpyrrolidine using using Method I. Deprotection of BOC group with HCl gasusing Method O followed by reaction with2-[2-(R,S)-1-(4-chloro-2,5-dimethyl-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid using Method I led to the title compound.

¹H NMR (DMSO-d₆) δ=1.65-2.10(m, 4H), 1.99(s, 3H), 2.20(s, 3H), 2.60(m,2H), 2.91(m, 2H), 3.21(m, 4H), 4.67(q, 1H), 4.77(dd, J=5.1 Hz, 1H),6.76-7.39(m, Ar—H, 8H), 8.38(d, J=4.8 z, 1H), 8.42(d, 2H), 10.40(bs,1H);

MS (ES): m/e 611 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=4.10 and 4.34 min.

Example 298 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-{2-[N-(pyrid-4-yl)piperidin-4-yl]eth-1-yl}acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(piperidin-4-yl)eth-1-yl]acetamidereacted with 4-chloropyridine using Method N to affford the titlecompound.

¹H NMR (DMSO-d₆) δ=1.04-1.22 (m, 4H), 1.90-2.20(m, 4H),1.95(s, 3H),2.19(s, 3H), 2.90(m, 2H), 3.14(br. t, 2H), 4.22(bd, 2H), 4.86(dd, J=4.5Hz), 6.79-7.45(m, Ar—H, 8H), 7.89(t, J=5.4 Hz, 1H), 8.16(d, 2H),10.44(s, 1H);

MS (ES): m/e 597 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=4.59 min.

Example 299 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(N-methylpiperidin-4-yl)-1-(R)-(pyrrolidin-N-ylcarbonyl)eth-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)-1-(R)-(pyrrolidin-N-ylcarbonyl)eth-1-yl]acetamidewas converted to the title compound using Methods J and K.

¹H NMR (DMSO-d₆) δ=1.10-1.85(m, 10H),1.86 (s, 3H), 2.16(s, 3H),2.0-2.50(m, 2H), 2.61(s, 3H) 3.0-3.43(m, 10H), 4.57(m, 1H), 4.81(br.dd,1H), 6.74-7.36(m, Ar—H, 6H), 8.20(br t, 1H), 10.39(s, 1H);

MS (ES): m/e 631 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=4.19 and 4.53 min.

Example 300 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(4-methylpiperazin-1-yl)eth-1-yl]acetamide

2-Chloro-ethylamine-hydrochloride reacted with 1-methylpiperazine inwater. After evaporation of water, the resulting amine was reacted with2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]aceticacid using Method I.

¹H NMR (DMSO-d₆) δ=2.04 (s, 3H), 2.10-2.40 (m, 2H), 2.27 (s, 3H), 2.80(s, 3H), 2.6-3.5 (bm, 6H), 4.93 (dd, J=3.9 Hz), 6.86-7.50 (m, Ar—H, 6H),8.15 (bt, 1H), 10.53 (s, 1H).

MS (ES): m/e 535 (M+H).

Example 301 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(N-cyclopropylpiperidin-4-yl)-1-(R)-(pyrrolidin-N-ylcarbonyl)eth-1-yl]acetamide

2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)-1-(R)-(pyrrolidin-N-ylcarbonyl)eth-1-yl]acetamidewas hydrogenated with PtO₂ using Method L to afford the title compound.

¹H NMR (DMSO-d₆) δ=0.20 (bd, 2H), 0.40 (bd, 2H), 1.0-2.0 (m, 12H), 1.90(s, 3H), 2.18 (s, 3H), 2.0-2.50 (m, 4H), 2.84 (m, 4H), 3.0-3.5 (m, 4H),4.55 (m, 1H), 6.76 (m, Ar—H, 6H), 8.12 (bdd, 1H), 10.39 (s, 1H);

MS (ES): m/e 657 (M+H).

Example 302 Preparation of2-[2-(R,S)-1-(2-chloro-4-fluorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(pyrid-4-yl)ethylacetamideand 2-chloro-4-fluorobenzenesulfonylchloride using Method H′.

MS (ES): m/e 503.3 (M+H)

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=2.29 min.

Example 303 Preparation of2-[2-(R,S)-1-(2,4,6-triisopropylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pydrid-4-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(pyrid-4-yl)ethylacetamideand 2,4,6-tri-iso-propyl-benzenesulfonyl chloride using Method H′.

MS (ES): m/e 577.3 (M+H)

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=3.00 min.

Example 304 Preparation of2-[2-(R,S)-1-(5-dimethylamino-napthalenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(pyrid-4-yl)ethylacetamideand 5-dimethylamino-naphthalenesulfonyl chloride using Method H′.

MS (ES): m/e 544.4 (M+H)

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=2.41 min.

Example 305 Preparation of2-[2-(R,S)-1-(2-methoxy-5-methylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(pyrid-4-yl)ethylacetamideand 2-methoxy-5-methylbenzene-sulfonyl chloride using Method H′.

MS (ES): m/e 495.3 (M+H)

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=2.28 min.

Example 306 Preparation of2-[2-(R,S)-1-(2-cyanobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(pyrid-4-yl)ethylacetamideand 2-cyanobenzene-sulfonyl chloride using Method H′.

MS (ES): m/e 476.3 (M+H)

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=2.07 min.

Example 307 Preparation of2-[2-(R,S)-1-(2-fluorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(pyrid-4-yl)ethylacetamideand 2-fluorobenzene-sulfonyl chloride using Method H′.

MS (ES): m/e 469.3 (M+H)

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=2.13 min.

Example 308 Preparation of2-[2-(R,S)-1-(2-methoxy-4-methylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(pyrid-4-yl)ethylacetamideand 2-methoxy-4-methylbenzene-sulfonyl chloride using Method H′.

MS (ES): m/e 495.3 (M+H)

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=2.31 min.

Example 309 Preparation of2-[2-(R,S)-1-(2,5-dimethoxybenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(pyrid-4-yl)ethylacetamideand 2,5-dimethoxybenzene-sulfonyl chloride using Method H′.

MS (ES): m/e 511.3 (M+H)

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=2.20 min.

Example 310 Preparation of2-[2-(R,S)-1-(2,4-difluorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(pyrid-4-yl)ethylacetamideand 2,4-difluoro-benzenesulfonyl chloride using Method H′.

MS (ES): m/e 487.3 (M+H)

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=2.20 min.

Example 311 Preparation of2-[2-(R,S)-1-(2-methoxy-5-bromobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(pyrid-4-yl)ethylacetamideand 2-methoxy-5-bromobenzene-sulfonyl chloride using Method H′.

MS (ES): m/e 560.3 (M+H)

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=2.35 min.

Example 312 Preparation of2-[2-(R,S)-1-(2,3-dimethyl-imidazole-5-ylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(pyrid-4-yl)ethylacetamideand 2,3-dimethyl-imidazole-5-ylsulfonyl chloride using Method H′.

MS (ES): m/e 469.3 (M+H)

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=1.61 min.

Example 313 Preparation of2-[2-(R,S)-1-(2-acetamido-4-methyl-thiazol-5-ylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(pyrid-4-yl)ethylacetamideand 2-acetamido-4-methylthiazol-5-ylsulfonyl chloride using Method H′.

MS (ES): m/e 529.3 (M+H)

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=2.11 min.

Example 314 Preparation of2-[2-(R,S)-1-(quinolin-8-ylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(pyrid-4-yl)ethylacetamideand quinolin-8-ylsulfonyl chloride using Method H′.

MS (ES): m/e 502.2 (M+H)

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=2.17 min.

Example 315 Preparation of2-[2-(R,S)-1-(thiophen-2-ylsulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(pyrid-4-yl)ethylacetamideand thiophen-2-ylsulfonyl chloride using Method H′.

MS (ES): m/e 457.2 (M+H)

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=2.08 min.

Example 316 Preparation of2-[2-(R,S)-1-(2-methoxycarbonyl-thiophen-3-ylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(pyrid-4-yl)ethylacetamideand 2-methoxycarbonyl-thiophen-3-ylsulfonyl chloride using method H′.

MS (ES): m/e 515.3 (M+H)

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=2.08 min.

Example 317 Preparation of2-[2-(R,S)-1-(2,5-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(pyrid-4-yl)ethylacetamideand 2,5-dichloro-benzenesulfonyl chloride using method H′.

MS (ES): m/e 520.2 (M+H)

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=2.40 min.

Example 318 Preparation of2-[2-(R,S)-1-(4-bromo-2-ethyl-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(pyrid-4-yl)ethylacetamideand 4-bromo-2-ethylbenzene-sulfonyl chloride using method H′.

MS (ES): m/e 558.3 (M+H)

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=2.55 min.

Example 319 Preparation of2-[2-(R,S)-1-(5-chloro-2-methoxybenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(pyrid-4-yl)ethylacetamideand 5-chloro-2-methoxybenzene-sulfonyl chloride using method H′.

MS (ES): m/e 515.3 (M+H)

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=2.33 min.

Example 320 Preparation of2-[2-(R,S)-1-(2-chloro-4-trifluoromethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(pyrid-4-yl)ethylacetamideand 2-chloro-4-trifluoromethyl-benzenesulfonyl chloride using method H′.

MS (ES): m/e 553.3 (M+H)

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=2.51 min.

Example 321 Preparation of2-[2-(R,S)-1-(2,4-dichloro-5-methylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(pyrid-4-yl)ethylacetamideand 2,4-dichloro-5-methylbenzenesulfonyl chloride using method H′.

MS (ES): m/e 534.3 (M+H)

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=2.52 min.

Example 322 Preparation of2-[2-(R,S)-1-(4-bromo-2-trifluoromethoxybenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(pyrid-4-yl)ethylacetamideand 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride using method H′.

MS (ES): m/e 614.2 (M+H)

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=2.56 min.

Example 323 Preparation of2-[2-(R,S)-1-(2-chloro-4-cyanobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(pyrid-4-yl)ethylacetamideand 2-chloro-4-cyanobenzene-sulfonyl chloride using method H′.

MS (ES): m/e 510.3 (M+H)

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=2.35 min.

Example 324 Preparation of2-[2-(R,S)-1-(5-fluoro-2-methylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(pyrid-4-yl)ethylacetamideand 5-fluoro-2-methyl-benzenesulfonyl chloride using method H′.

MS (ES): m/e 483.3 (M+H)

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=2.31 min.

Example 325 Preparation of2-[2-(R,S)-1-(2-nitrobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(pyrid-4-yl)ethylacetamideand 2-nitrobenzene-sulfonyl chloride using Method H′.

MS (ES): m/e 496.3 (M+H)

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=2.19 min.

Example 326 Preparation of2-[2-(R,S)-1-(2-trifluoromethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(pyrid-4-yl)ethylacetamideand 2-trifluoro-methylbenzene-sulfonyl chloride using Method H′.

MS (ES): m/e 519.1 (M+H)

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=2.40 min.

Example 327 Preparation of2-[2-(R,S)-1-(3-N-methylimidazol-5-ylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(pyrid-4-yl)ethylacetamideand 3-N-methylimidazol-5-ylsulfonyl chloride using Method H′.

MS (ES): m/e 455.3 (M+H)

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=2.20 min.

Example 328 Preparation of2-[2-(R,S)-1-(3,5-dimethyl-isooxazol-4-ylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(pyrid-4-yl)ethylacetamideand 3,5-dimethyl-isooxazol-4-ylsulfonyl chloride using Method H′.

MS (ES): m/e 470.2 (M+H)

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=2.12 min.

Example 329 Preparation of2-[2-(R,S)-1-(N-morpholinosulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(pyrid-4-yl)ethylacetamideand N-morpholino-sulfonyl chloride using Method H′.

MS (ES): m/e 460.2 (M+H)

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=2.10 min.

Example 330 Preparation of2-[2-(R,S)-1-(2,5-dibromobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(pyrid-4-yl)ethylacetamideand 2,5-dibromo-benzenesulfonyl chloride using method H′.

MS (ES): m/e 609.1 (M+H)

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=2.45 min.

Example 331 Preparation of2-[2-(R,S)-1-(2,3,4,5,6-pentamethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(pyrid-4-yl)ethylacetamideand 2,3,4,5,6-pentamethylbenzenesulfonyl chloride using method H′.

MS (ES): m/e 521.3 (M+H)

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=2.61 min.

Example 332 Preparation of2-[2-(R,S)-1-(4-bromo-2,5-difluorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(pyrid-4-yl)ethylacetamideand 4-bromo-2,5-difluorobenzene-sulfonyl chloride using method H′.

MS (ES): m/e 566.2 (M+H)

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=2.49 min.

Example 333 Preparation of2-[2-(R,S)-1-(2,3,5,6-tetramethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(pyrid-4-yl)ethylacetamideand 2,3,5,6-tetramethylbenzenesulfonyl chloride using method H′.

MS (ES): m/e 507.3 (M+H)

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=2.52 min.

Example 334 Preparation of2-[2-(R,S)-1-(2-chloro-6-methylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(pyrid-4-yl)ethylacetamideand 2-chloro-6-methyl-benzenesulfonyl chloride using method H′.

MS (ES): m/e 499.3 (M+H)

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=2.32 min.

Example 335 Preparation of2-[2-(R,S)-1-(2-chlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(pyrid-4-yl)ethylacetamideand 2-chlorobenzenesulfonyl chloride using method H′.

MS (ES): m/e 485.3 (M+H)

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=2.21 min.

Example 336 Preparation of2-[2-(R,S)-1-(2,4,5-trichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(pyrid-4-yl)ethylacetamideand 2,4,5-trichlorobenzenesulfonyl chloride using method H′.

MS (ES): m/e 554.3 (M+H)

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=2.55 min.

Example 337 Preparation of2-[2-(R,S)-1-(2-methyl-5-nitrobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(pyrid-4-yl)eth-1-yl]acetamide

The title compound was synthesized from2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(pyrid-4-yl)ethylacetamideand 2-methyl-5-nitrobenzene-sulfonyl chloride using method H′.

MS (ES): m/e 510.3 (M+H)

HPLC (CH₃CN—H₂O-0.1% TFA): R_(t)=2.35 min.

Example 338 Preparation of2-[2-(R)-1-(2,3-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetra-hydroquinoxalin-2-yl]-N-[2-(N-(1-pyridin-2-yl)piperidin-4-yl)eth-1-yl]acetamide

The title compound was synthesized from (R)-1-[(2,3-dichloro-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]acetic acid and2-[1-(pyrid-2-yl)piperidin-4-yl]ethylamine (described in Method K′)using Method S′.

MS (ES) m/e 602 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column) R_(t)=2.732 min.

Example 339 Preparation of2-[2-(R)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(1-aminophen-4-yl)eth-1-yl]acetamide

The title compound was synthesized from(R)-1-[(4-chloro-2,3-dimethyl-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and 4-amino phenethylamine (Aldrich) using Method S′.

MS (ES) m/e 527 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column) R_(t)=2.956 min.

Example 340 Preparation of2-[2-(R)-1-(2,3-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(N-(4-methylpyridin-2-yl)piperidin-4-yl)eth-1-yl]acetamide

The title compound was synthesized using(R)-1-[(2,3-dichlorobenzene-sulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]aceticacid and 2-[1-(4-methyl-pyrid-2-yl)piperidin-4-yl]ethylaminehydrochloride salt using Method S′. The amine was synthesized fromN-t-butoxycarbonyl 2-(piperidin-2-yl)ethylamine and 4-methyl-2-fluoropyridine (Aldrich), using Method K′.

MS (ES) m/e 616 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column) R_(t)=2.920 min.

Example 341 Preparation of2-[2-(R)-1-(2,3-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(N-(3-methylpyridin-2-yl)piperidin-4-yl)eth-1-yl]acetamide

The title compound was synthesized using (R)-1-[(2,3-dichloro-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]acetic acid and2-[1-(3-methyl-pyrid-2-yl)piperidin-4-yl]ethylamine hydrochloride saltusing Method S′. The amine was synthesized from N-t-butoxycarbonyl2-(piperidin-2-yl)ethylamine and 3-methyl-2-fluoro pyridine (Aldrich),using Method K′.

MS: (ES) m/e 616 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column) R_(t)=2.907 min.

Example 342 Preparation of2-[2-(R)-1-(2,3-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(N-(6-methylpyridin-2-yl)piperidin-4-yl)eth-1-yl]acetamide

The title compound was synthesized using (R)-1-[(2,3-dichloro-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]acetic acid and2-[1-(6-methyl-pyrid-2-yl)piperidin-4-yl]ethylamine hydrochloride saltusing Method S′. The amine was synthesized from N-t-butoxycarbonyl2-(piperidin-2-yl)ethylamine and 6-methyl-2-fluoro pyridine (Aldrich),using Method K′.

MS (ES) m/e 616 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column) R_(t)=2.872 min.

Example 343 Preparation of2-[2-(R)-1-(2,3-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-ethyl-N-[2-(N-(6-methylpyridin-2-yl)piperidin-4-yl)eth-1-yl]acetamide

The title compound was synthesized using (R)-1-[(2,3-dichloro-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]acetic acid and2-(N-ethyl)-[1-(6-methyl-pyrid-2-yl)piperidin-4-yl]ethylaminehydrochloride salt using Method S′. The amine was synthesized from2-(N-ethyl)-eth-1-yl-pyridine using Method T′, followed by Method K′,using N-ethyl-t-butoxycarbonyl 2-(piperidin-2-yl)ethyl amine, instead ofN-t-butoxycarbonyl 2-(piperidin-2-yl)ethyl amine and 6-methyl-2-fluoropyridine (Aldrich).

MS (ES) m/e 644 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column) R_(t)=3.139 min.

Example 344 Preparation of2-[2-(R)-1-(2,3-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-ethyl-N-[2-(N-(1-pyridin-2-yl)piperidin-4-yl)eth-1-yl]acetamide

The title compound was synthesized using (R)-1-[(2,3-dichloro-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]acetic acid and2-(N-ethyl)-[1-(pyrid-2-yl)piperidin-4-yl]ethylamine hydrochloride saltusing Method S′. The amine was synthesized from2-(N-ethyl)-eth-1-yl-pyridine using Method T′, followed by Method K′,using N-ethyl-t-butoxycarbonyl 2-(piperidin-2-yl)ethyl amine, instead ofN-t-butoxycarbonyl 2-(piperidin-2-yl)ethyl amine and 2-fluoro pyridine(Aldrich).

MS (ES) m/e 630 (M+H);

HPLC (CH₃CN—H₂O-0.1% TFA) (short column) R_(t)=3.014 min.

Example 345 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(2-methylpyridin-4-yl)eth-1-yl]acetamide

A solution ofR-[1-(4-chloro-2,5-dimethyl-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]-aceticacid (150 mg, 0.37 mmol), 2-(2-methyl-pyridin-4-yl)-ethylamine(described in Method V′) (87.4 mg, 0.64 mmol) and triethyl amine (230μL, 1.65 mmol) in 3 mL of acetonitrile was treated with HATU (153 mg,0.4 mmol). The resulting solution was stirred several hours at roomtemperature, concentrated and chromatographed to give pure titlecompound.

MS(ES): m/e (EI*) 527.1 [M+H]

Example 346 Preparation of2-[2-(R,S)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-(benzoimidazol-2-ylamino)eth-1-ylacetamide

A mixture of N1-(1H-benzoimidazol-2-yl)-ethane-1,2-diamine (113 mg),described in MethodW′,R-[1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]-aceticacid, and triethyl amine (230 μL) in 5 mL of acetonitrile, with a smallamount of DMF added for solubility, was treated with HATU (153 mg). Theresulting homogeneous solution was stirred at room temperature for 2hours then concentrated and diluted with a mixture of choroform andisopropanol (3:1). The organic layer was washed with saturated aqueousodium bicarbonate solution and brine, dried in vacuo, and concentrated.The residue was purified by HPLC.

MS(ES): m/e (EI*) 566.2 [M+H]

Example 347 Preparation of2-[2-(R)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[3-(benzoimidazol-2-ylamino)prop-1-yl]acetamide

The title compound was prepared in the same manner as that described forExample 362 after HPLC purification, fromN1-(1H-benzoimidazol-2-yl)-ethane-1,3-diamine andR-[1-(4-chloro-2,5-dimethyl-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]-aceticacid. N1-(1H-benzoimidazol-2-yl)-ethane-1,3-diamine was obtained from1,3-diamine using Method W′.

MS(ES): m/e (EI*) 580.2 [M+H]

Example 348 Preparation of2-[2-(R)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-(1-(pyrid-2-yl)phen-4-yl)eth-1-v]acetamide

R-[1-(4-Chloro-2,5-dimethyl-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]aceticacid and 2-(4-Pyridin-2-yl-phenyl)-ethylamine were reacted using MethodU′ to give the title compound. This was then purified by columnchromatography over silica gel with EtOAc (100%) as eluent.

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=3.09 min.

Example 349 Preparation of2-[2-(R)-1-(2,3-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-methyl-N-[2-(pyridin-4-yl)eth-1-yl]acetamide

R-[1-(2,3-Dichloro-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-qinoxalin-2-yl]-aceticacid and N-methyl-(2-pyridin-4-yl-ethyl)-amine (Array) were reactedusing Method U′ to give the title compound. The solvent was removedunder vacuum and the crude residue dissolved in CH₂Cl₂ (25 mL). Theorganic layer was washed with brine (4×20 mL) and dried over Na₂SO₄. Thesolvent was removed under vacuum and the crude mixture purified bycolumn chromatography over silica gel with 0.5%-2% MeOH/CH₂Cl₂ aseluent.

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=2.49 min.

Example 350 Preparation of2-[2-(R)-1-(2,3-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-isopropyl-N-[2-(pyridin-4-yl)eth-1-yl]acetamide

R-[1-(2,3-Dichloro-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-qinoxalin-2-yl]aceticacid and N-isopropyl-(2-pyridin-4-yl-ethyl)-amine, obtained as describedin Method U, were reacted using Method U′ to give the title compound.The solvent was removed under vacuum and the crude residue dissolved inCH₂Cl₂ (25 mL). The organic layer was washed with brine (4×20 mL) anddried over Na₂SO₄. The solvent was removed under vacuum and thenpurified by column chromatography over silica gel EtOAc (100%) aseluent.

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=3.06 min.

Example 351 Preparation of2-[2-(R)-1-(2,3-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-ethyl-N-[2-(pyridin-4-yl)eth-1-yl]acetamide

R-[1-(2,3-Dichloro-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-qinoxalin-2-yl]-aceticacid and N-ethyl-(2-pyridin-4-yl-ethyl)-amine trifluoroacetate salt(Method X′), obtained from vinyl pyridine using Method T′, were reactedusing Method S′ to give the title compound. Brine (50 mL) was added at−20° C., extracted with CH₂Cl₂ (50 mL) and dried over Na₂SO₄. Thesolvent was removed under vacuum and then purified by columnchromatography over silica gel with 0.5%-3% MeOH/CH₂Cl₂ as eluent.

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=2.62 min.

Example 352 Preparation of2-[2-(R)-1-(2,3-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-ethyl-N-[2-(N-methyl-piperidin-4-yl)eth-1-yl]acetamide

The pyridinium salt of2-[2-(R)-1-(2,3-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-ethyl-N-[2-(pyridin-4-yl)eth-1-yl]acetamidewas formed using Method J and taken on without purification to the nextstep. Reduction of the methyl iodide salt with excess PtO₂ in MeOH wasperformed under 54 psi at room temperature overnight. The crude mixturewas filtered over celite. Upon evaporation of the solvent under reducedpressure, the residue was dissolved in EtOH and cooled to 0° C. HCl wasthen added dropwise to a pH=3. The solvent was then removed under vacuumwithout heat to give the title compound as the HCL salt.

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=2.71 min.

Example 353 Preparation of2-[2-(R)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-[N-(3-methylpyridin-2-yl)piperidin-4-yl]eth-1-yl]acetamide

The title compound was synthesized using(R)-1-[(4-chloro-2,5-dimethyl-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]aceticacid and 2-[1-(3-methyl-pyrid-2-yl)piperidin-4-yl]ethylaminehydrochloride salt using Method U′. The amine was synthesized fromN-t-butoxycarbonyl 2-(piperidin-2-yl)ethylamine and 3-methyl-2-fluoropyridine (Aldrich), using Method K′.

MS (ES): m/e 611 (M+H).

Example 354 Preparation of2-[2-(R)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[2-[N-(4-methylpyridin-2-yl)piperidin-4-yl]eth-1-yl]acetamide

The title compound was synthesized using(R)-1-[(4-chloro-2,5-dimethyl-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]acetic acid and2-[1-(4-methyl-pyrid-2-yl)piperidin-4-yl]ethylamine hydrochloride saltusing Method U′. The amine was synthesized from N-t-butoxycarbonyl2-(piperidin-2-yl)ethylamine and 4-methyl-2-fluoro pyridine (Aldrich),using Method K′.

MS (ES): m/e 611 (M+H).

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=3.19 min

Example 355 Preparation of2-[2-(R-1-(2,3-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-methyl-N-[2-(N-methyl-piperidin-4-yl)eth-1-yl]acetamide

The title compound was synthesized using(R,S)-1-[(4-chloro-2,5-dimethyl-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]acetic acid and2-N-methyl-[1-(N-methyl)piperidin-4-yl]ethylamine hydrochloride saltusing Method I. The amine was synthesized fromN-methyl-(2-pyridin-4-yl-ethyl)amine (Array) using Method J. The crudematerial was purified on prep HPLC.

MS (ES): m/e 554 (M+H).

Example 356 Preparation of2-[2-(R)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[4-(pyrid-2-yl)but-3-yn-1-yl]acetamide

The title compound was synthesized using(R,S)-1-[(4-chloro-2,5-dimethyl-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]aceticacid and 4-(pyridin-2-yl)but-3-yn-1ylamine hydrochloride salt usingMethod U′. The amine was obtained from pent-4-ynoic acid using MethodY′. MS (ES): m/e 537 (M+H).

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=2.85 min

Example 357 Preparation of2-[2-(R)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]-N-[4-(pyrid-2-yl)but-3-yn-1-yl]acetamide

The title compound was synthesized using(R,S)-1-[(4-chloro-2,5-dimethyl-benzenesulfonyl)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]acetic acid and4-(pyridin-2-yl)but-3-yn-1ylamine hydrochloride salt using Method U′.The amine was obtained from pent-4-ynoic acid using Method Y′, replacing4-bromopyridine with 2-bromo pyridine (Aldrich).

MS (ES): m/e 537 (M+H).

HPLC (CH₃CN—H₂O-0.1% TFA) (short column): R_(t)=2.86 min

Biological Example

The potency and efficacy to inhibit the bradykinin B1 receptor wasdetermined for the compounds of this invention in a cell-basedfluorescent calcium-mobilization assay. The assay measures the abilityof test compounds to inhibit B1 agonist-induced increase ofintracellular free Ca⁺² in a native human B1 receptor-expressing cellline.

In this example, the following additional abbreviations have themeanings set forth below. Abbreviations heretofore defined are asdefined previously. Undefined abbreviations have there art recognizedmeanings.

-   -   BSA=bovine serum albumin    -   DMSO=dimethylsulfoxide    -   FBS=fetal bovine serum    -   MEM=minimum essential medium    -   mM=millimolar    -   ng=nanogram    -   μg=micrograms    -   μM=micromolar

Specifically, calcium indicator-loaded cells are pre-incubated in theabsence or presence of different concentrations of test compoundsfollowed by stimulation with selective B1 agonist peptide whileCa-dependent fluorescence is monitored.

IMR-90 human lung fibroblast cells (CCL 186, American Type TissueCollection) are grown in MEM supplemented with 10% FBS as recommended byATCC. Confluent cells are harvested by trypsinization and seeded intoblack wall/clear bottom 96-well plates (Costar #3904) at approx. 13,000cells/well. The following day, cells are treated with 0.35 ng/mLinterleukin-113 in 10% FBS/MEM for 2 hours to up-regulate B1 receptors.Induced cells are loaded with fluorescent calcium indicator byincubation with 2.3 μM Fluo-4/μM (Molecular Probes) at 37° C. for 1.5hrs in the presence of an anion transport inhibitor (2.5 mM probenecidin 1% FBS/MEM). Extracellular dye is removed by washing with assaybuffer (2.5 mM probenecid, 0.1% BSA, 20 mM HEPES in Hank's Balanced SaltSolution without bicarbonate or phenol red, pH 7.5) and cell plates arekept in dark until used. Test compounds are assayed at 7 concentrationsin triplicate wells. Serial dilutions are made in half log-steps at100-times final concentration in DMSO and then diluted in assay buffer.Compound addition plates contain 2.5-times final concentrations of testcompounds or controls in 2.5% DMSO/assay buffer. Agonist plates contain5-times the final concentration of 2.5 nM (3×EC50) B1 agonist peptidedes-Arg¹⁰-kallidin (DAKD, Bachem) in assay buffer. Addition of testcompounds to cell plate, incubation for 5 min at 35° C., followed by theaddition of B1 agonist DAKD is carried out in the Fluorometric ImagingPlate Reader (FLIPR, Molecular Devices) while continuously monitoringCa-dependent fluorescence. Peak height of DAKD-induced fluorescence isplotted as function of concentration of test compounds. IC₅₀ values arecalculated by fitting a 4-parameter logistic function to theconcentration-response data using non-linear regression (Xlfit, IDBS).

Typical potencies observed for B1 receptor agonist peptides areEC₅₀=approx. 0.8 nM and approx. 100 nM for des-Arg¹⁰-kallidin anddes-Arg⁹-bradykinin, respectively, while for B1 antagonist peptidedes-Arg¹⁰, Leu⁹-kallidin IC₅₀ is approx. 1 nM.

The compounds of this invention, including those of Formula I, as wellas the commercially available compounds of Examples 79 and 80 exhibitedIC₅₀ values of 0.1 to 10,000 nM in this assay.

In view of the above, all of these compounds exhibit B1 antagonisticproperties and, accordingly, are useful in treating disease conditionsmediated at least in part by B1.

1. A compound of Formula I:

wherein one of bonds characterized by

is a double bond and the other two are single bonds; n is an integerfrom 0 to 4; p is zero or one; q is zero or one; Y is selected from thegroup consisting of ═O, ═S, —OR⁸,—NHR⁸, ═NR⁸, —SR⁸, and, when Y is —NHR⁸or ═NR⁸, R⁷ and R⁸, together with the nitrogen atoms to which they areattached, can form a heteroaryl, a substituted heteroaryl, anunsaturated heterocyclic, or a substituted unsaturated heterocyclic;provided that: when Y is ═O, ═S, or ═NR⁸, then the bonds characterizedby

between the 2-3 and 3-4 position are single covalent bonds and p is one;when Y is —OR⁸, —SR⁸, or —NHR⁸ and p is zero, then the bondcharacterized by

between the 3-4 position is a double bond; or when Y is —OR⁸, —SR⁸, or—NHR⁸ and p=1 and R⁷ is other than hydrogen, then the bond characterizedby

between the 2-3 position is a double bond; W is selected from the groupconsisting of O, S, and N, wherein: when W is O or S, then q is zero;and when W is N, then q is one; R is selected from the group consistingof aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic and substituted heterocyclic; R¹ and R² are independentlyselected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl,substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic, or R¹and R² together with the nitrogen atom to which they are attached form aheteroaryl, substituted heteroaryl, heterocyclic, or substitutedheterocyclic; each R³ is independently selected from the groupconsisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, amino, substituted amino, cycloalkyl,substituted cycloalkyl, alkoxy, substituted alkoxy, aryl, substitutedaryl, aryloxy, substituted aryloxy, heteroaryl, substituted heteroaryl,heteroaryloxy, substituted heteroaryloxy, heterocyclic, substitutedheterocyclic, heterocyclyloxy, substituted heterocyclyloxy, acyl,acyloxy, halogen, nitro, cyano, hydroxy, carboxy, —C(O)OR¹⁰ wherein R¹⁰is alkyl, substituted alkyl, aryl, or substituted aryl, and —C(O)NR¹¹R¹²wherein R¹¹ and R¹² are independently selected from the group consistingof hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl,heterocyclic and substituted heterocyclic, or R¹¹ and R¹² together withthe nitrogen atoms to which they are joined form a heteroaryl,substituted heteroaryl, heterocyclic a substituted heterocyclic group;or two or more of R³ together with the carbon atoms to which they arejoined form a fused ring cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, unsaturatedheterocyclic or substituted unsaturated heterocyclic; R⁷ is selectedfrom the group consisting of hydrogen, alkyl, substituted alkyl,alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic,substituted heterocyclic, acyl and acyloxy; or R⁷ together with at leastone of R³ and the nitrogen and carbon atoms to which they are joinedforms a fused ring heteroaryl, substituted heteroaryl, unsaturatedheterocyclic or substituted unsaturated heterocyclic; R⁸ is selectedfrom the group consisting of alkyl, substituted alkyl, alkenyl,substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroayl, substituted heteroaryl, heterocyclic,substituted heterocyclic, acyl and acyloxy; and pharmaceuticallyacceptable salts thereof; with the proviso that when W═N and Y═O, atleast R¹ and/or R² is selected from the group consisting of I-alkylene-C(═O)R^(a), wherein alkylene is optionally substituted andR^(a) is selected from the group consisting of hydroxyl, —NR^(b)R^(b),—OR^(b), alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl,substituted cycloalkyl, heteroaryl, substituted heterocyclyl,substituted heterocyclyl wherein each R^(b) is independently selectedfrom the group consisting of hydrogen, alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl,substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic; II-alkylene-X^(a), wherein alkylene is optionally substituted and X^(a) isselected from the group consisting of —OH, cyano, and —NR^(b)R^(b)wherein each R^(b) is independently as defined above; III -NHR^(b),wherein R^(b) is as defined above; IV -OR^(b), wherein R^(b) is asdefined above; V -alkylene-het^(a)-C(═O)—CH(R^(b))NR^(b)R^(b), whereinalkylene is optionally substituted and het^(a) is a nitrogen containingheterocycyl attached to the —C(O)— group through a ring nitrogen atom ofthe het^(a) group and each R^(b) is as defined above; VI-alkylene-het^(a)-C(═O)-het^(b), wherein alkylene is optionallysubstituted and het^(a) is as defined above and het^(b) is aheterocyclyl; VII -alkylene-R^(c)—NR^(b)C(═NR b)NR^(b)R^(b), whereinalkylene is optionally substituted, each R^(b) is as defined above andR^(c) is selected from the group consisting of aryl, substituted aryl,cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl,heterocyclic and substituted heterocyclic; VIII-alkylene-R^(c)—NR^(b)C(═O)—NR^(b)R^(b), wherein alkylene is optionallysubstituted, each R^(b) is as defined above and R^(c) is as definedabove; IX -alkylene-R^(c)-alkylene-C(═O)R^(b), wherein alkylene isoptionally substituted and R^(b) and R^(c) are as defined above; Xalkylene-R^(c)—C(═O)-alkylene-(X^(b))_(n), wherein alkylene isoptionally substituted, X^(b) is selected from the group consisting of—OH, halo, cyano, and —NR^(b)R^(b), n is one except when X^(b) is halothen n can be 1-3; and further wherein each R^(b) is independently asdefined above and R^(c) is as defined above; XI-alkylene-R^(c)—C(═O)—R^(d), wherein alkylene is optionally substitutedand R^(c) is selected from the group consisting of aryl, substitutedaryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic and R^(d) isselected from the group consisting of substituted alkyl, aryl,heteroaryl, heterocyclic and cycloalkyl; XII-alkylene-R^(c)—NR^(b)C(═O)R^(e) wherein alkylene is optionallysubstituted, R^(b) and R^(c) are as defined above, and where R^(e) issubstituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl,cycloalkyl, substituted heteroaryl; XIII -alkynylene-R^(d) where R^(d)is as defined above; XIV or where R¹ and R² are joined, together withthe nitrogen atom bond thereto, to form a nitrogen containingsubstituted heterocyclyl with 1 to 2 substituents selected fromsubstituted alkyl, heteroaryl, heterocyclyl; XV -alkenylene-R^(d) whereR^(d) is as defined above; and XVI-alkylene-R^(c)—NR^(b)—C(═NR^(b))R^(b), wherein alkylene is optionallysubstituted, and each of R^(b) and R^(c) are as defined above; with thefurther provisos that: A. when W is N, R¹ is hydrogen, R² is benzyl, R⁷is methyl, n is zero, p is one, and Y is ═O, then R is not2,4,6-trimethylphenyl; B. when W is N, R¹ and R⁷ are hydrogen, R² is2-(pyrid-4-yl)ethy-1-yl, n is zero, p is one, and Y is ═O, then R is not1-methylpyrazol-4-yl; C. when W is N, R¹ and R⁷ are hydrogen, R² isbenzyl, n is zero, p is one, and Y is ═O, then R is not2,4-difluorophenyl; D. when W is N, R¹, R² and R⁷ are hydrogen, n iszero, p is one, and Y is ═O, then R is not 2,4-difluorophenyl; E. when Wis N, R¹ is hydrogen, R² and R⁷ are 3-chlorobenzyl, n is zero, p is one,and Y is ═O, then R is not 4-chloro-2,5-dimethylphenyl; F. when W is N,R¹ and R⁷ are hydrogen, R² is benzyl, n is zero, p is one, and Y is ═O,then R is not phenyl; G. when W is N, R¹ and R⁷ are hydrogen, R² isphenyl, n is zero, p is one, and Y is ═O, then R is not quinolin-8-yl;and H. when W is N, R ¹ and R⁷ are hydrogen, R² is benzyl, n is zero, pis one, and Y is ═O, then R is not thien-2-yl; and with the furtherproviso excluding the following known compounds: I. when R¹ and R⁷ arehydrogen, R² is 2-methoxyphenyl, n is zero, p is one, and Y′ is ═O, thenR is not 4-methylphenyl; and J. when R¹ and R⁷ are hydrogen, R² is2-ethoxyphenyl, n is zero, p is one, and Y′ is ═O, then R is not4-methylphenyl. 2-32. (canceled)
 33. A compound of Formula III

wherein one of bonds characterized by

is a double bond and the other two are single bonds; n is an integerfrom 0 to 4; p is zero or one; Y is selected from the group consistingof ═O, ═S, —OR⁸, —NHR⁸, ═NR⁸, —SR⁸, and, when Y is —NHR⁸ or ═NR⁸, R⁷ andR⁸, together with the nitrogen atoms to which they are attached, canform a heteroaryl, a substituted heteroaryl, an unsaturatedheterocyclic, or a substituted unsaturated heterocyclic; provided that:when Y is ═O, ═S, or ═NR⁸, then the bonds characterized by

between the 2-3 and 3-4 position are single covalent bonds and p is one;when Y is —OR⁸, —SR⁸, or —NHR⁸ and p is zero, then the bondcharacterized by

between the 3-4 position is a double bond; or when Y is —OR⁸, —SR⁸, or—NHR⁸ and p=1 and R⁷ is other than hydrogen, then the bond characterizedby

between the 2-3 position is a double bond; each R³ is independentlyselected from the group consisting of alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, amino, substitutedamino, cycloalkyl, substituted cycloalkyl, alkoxy, substituted alkoxy,aryl, substituted aryl, aryloxy, substituted aryloxy, heteroaryl,substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy,heterocyclic, substituted heterocyclic, heterocyclyloxy, substitutedheterocyclyloxy, acyl, acyloxy, halogen, nitro, cyano, hydroxy, carboxy,—C(O)OR¹⁰ wherein R¹⁰ is alkyl, substituted alkyl, aryl, or substitutedaryl, and —C(O)NR¹¹R¹² wherein R¹¹ and R¹² are independently selectedfrom the group consisting of hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic, orR¹¹ and R¹² together with the nitrogen atoms to which they are joinedform a heteroaryl, substituted heteroaryl, heterocyclic a substitutedheterocyclic group; or two or more of R³ together with the carbon atomsto which they are joined form a fused ring cycloalkenyl, substitutedcycloalkenyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, unsaturated heterocyclic or substituted unsaturatedheterocyclic; R⁷ is selected from the group consisting of hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, acyl and acyloxy; orR⁷ together with at least one of R³ and the nitrogen and carbon atoms towhich they are joined forms a fused ring heteroaryl, substitutedheteroaryl, unsaturated heterocyclic or substituted unsaturatedheterocyclic; R⁸ is selected from the group consisting of alkyl,substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substitutedcycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic, acyl and acyloxy; and X is—NR¹R² wherein R¹ and R² are joined, together with the nitrogen atombond thereto, to form a nitrogen containing substituted heterocyclylwith 1 to 2 substituents selected from the group consisting ofsubstituted alkyl, heteroaryl, and heterocyclyl; and pharmaceuticallyacceptable salts thereof.
 34. The compound of claim 33, wherein n iszero.
 35. The compound of claim 33, wherein n is one or two.
 36. Thecompound of claim 33, wherein R³ is selected from the group consistingof chloro, fluoro, and methyl.
 37. The compound of claim 33, wherein pis one and R⁷ is selected from the group consisting of hydrogen, methyl,benzyl, and t-butoxycarbonylmethyl.
 38. The compound of claim 33,wherein, Y is ═O.
 39. The compound of claim 33, wherein X is —NR¹R²wherein R¹ and R² are joined, together with the nitrogen atom bondthereto, to form an optionally substituted heterocyclyl selected fromthe group consisting of 4-(2-aminoethyl)piperidin-1-yl;4-[2-(N-t-butoxycarbonylamino)ethyl]-piperidin-1-yl; and1-(pyridine-2-yl)piperazin-4-yl.
 40. The compound of claim 39, whereinR³ is selected from the group consisting of chloro, fluoro, and methyl.41. The compound of claim 39, wherein p is one and R⁷ is selected fromthe group consisting of hydrogen, methyl, benzyl, andt-butoxycarbonylmethyl.
 42. The compound of claim 39, wherein, Y is ═O.43. A compound of Formula IIIa

n is an integer from 0 to 4; each R³ is independently selected from thegroup consisting of alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, amino, substituted amino,cycloalkyl, substituted cycloalkyl, alkoxy, substituted alkoxy, aryl,substituted aryl, aryloxy, substituted aryloxy, heteroaryl, substitutedheteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclic,substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy,acyl, acyloxy, halogen, nitro, cyano, hydroxy, carboxy, —C(O)OR¹⁰wherein R¹⁰ is alkyl, substituted alkyl, aryl, or substituted aryl, and—C(O)NR¹¹R¹² wherein R¹¹ and R¹² are independently selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic, orR¹¹ and R¹² together with the nitrogen atoms to which they are joinedform a heteroaryl, substituted heteroaryl, heterocyclic a substitutedheterocyclic group; or two or more of R³ together with the carbon atomsto which they are joined form a fused ring cycloalkenyl, substitutedcycloalkenyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl,unsaturated heterocyclic or substituted unsaturated heterocyclic; R⁷ isselected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkylaryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic, acyl and acyloxy; or R⁷ togetherwith at least one of R³ and the nitrogen and carbon atoms to which theyare joined forms a fused ring heteroaryl, substituted heteroaryl,unsaturated heterocyclic or substituted unsaturated heterocyclic; X is—NR¹R² wherein R¹ and R² are joined, together with the nitrogen atombond thereto, to form a nitrogen containing substituted heterocyclylwith 1 to 2 substituents selected from the group consisting ofsubstituted alkyl, heteroaryl, and heterocyclyl; and pharmaceuticallyacceptable salts thereof.
 44. The compound of claim 43, wherein n iszero.
 45. The compound of claim 43, wherein n is one or two.
 46. Thecompound of claim 43, wherein R³ is selected from the group consistingof chloro, fluoro, and methyl.
 47. The compound of claim 43, wherein R⁷is selected from the group consisting of hydrogen, methyl, benzyl, andt-butoxycarbonylmethyl.
 48. The compound of claim 43, wherein X is—NR¹R² wherein R¹ and R² are joined, together with the nitrogen atombond thereto, to form an optionally substituted heterocyclyl selectedfrom the group consisting of 4-(2-aminoethyl)piperidin-1-yl;4-[2-(N-t-butoxycarbonylamino)ethyl]-piperidin-1-yl; and1-(pyridine-2-yl)piperazin-4-yl.
 49. A compound of Formula IIIb

R⁷ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl,aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic, acyl and acyloxy; X is —NR¹R²wherein R¹ and R² are joined, together with the nitrogen atom bondthereto, to form a nitrogen containing substituted heterocyclyl with 1to 2 substituents selected from the group consisting of substitutedalkyl, heteroaryl, and heterocyclyl; and pharmaceutically acceptablesalts thereof.
 50. The compound of claim 49, wherein p is one and R⁷ isselected from the group consisting of hydrogen, methyl, benzyl, andt-butoxycarbonylmethyl.
 51. The compound of claim 49, wherein X is—NR¹R² wherein R¹ and R² are joined, together with the nitrogen atombond thereto, to form an optionally substituted heterocyclyl selectedfrom the group consisting of 4-(2-aminoethyl)piperidin-1-yl;4-[2-(N-t-butoxycarbonylamino)ethyl]-piperidin-1-yl; and1-(pyridine-2-yl)piperazin-4-yl.